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COVID-19 infection\n3.1 It is customary to divide the course of the infection into different stages: Preinfection (co-morbidities), asymptomatic, early clinical, severe clinical (acute respiratory distress syndrome–ARDS), and recovery [8,9], Fig. 2 . This natural timing should be used to establish key point-of-care sampling timepoints, avoiding patient discomfort and to focus resources. Infection can progress or be aborted at every stage, presenting a dynamic continuum, to which macrophages and monocytes contribute, together with other immune and non-immune elements; MPS contributions to COVID-19 resistance and pathogenesis are still underestimated and poorly understood.\nFig. 2 Decision points that determine the outcome of COVID-19 infection and requirements for a monocyte activation assay. A time and severity pattern has emerged for COVID-19 progression. The first days, first and second week timelines are turning points for resolution or deterioration. Epidemiologic precision for these milestones and precise parameters will be valuable for strategic sampling and patient stratification, sparing resources and patient material. With limited volumes of peripheral blood, a window on progression of the infection can be obtained by studying activation of the mononuclear phagocyte system, largely represented by monocytes in blood. The cells are biosynthetically active and relatively long lived, ideal to trace long term effects of comorbidities and infection. We highlight selected functional categories that should be addressed in monocytes and can be adapted to particular applications.\n\n3.2 Co-morbidities and the mps\nMacrophage activities contribute to many co- morbidities [8,9], including aging [28], obesity [29], diabetes [30], exposure to pollutants [31], and microbiome properties [32]. Macrophage functions alter with age, together with adaptive immune processes such as thymic involution, which deplete T lymphocyte reserves. Chronic, low grade inflammation (INFLAMMAGING) has been proposed as a predisposing factor [33]. This may result from failure of macrophages and NK cells to clear increasing accumulation of senescent cells, that enhance basal levels of inflammation and interfere with subsequent adaptive immunity upon infection [28]. Baseline inflammation may not be detrimental in itself, but can initiate an inflammatory cascade that amplifies excessive inflammation occurring in response to pathogens. Age-related metabolic correlates of macrophage dysfunction include innate lymphoid cell interactions with adipose tissue and associated macrophages, as well as inflammasome activation [34,35]. This affects thermogenesis, part of a wider metabolic syndrome involving glucose and lipid metabolism [36], elevated body mass index (BMI), type 1 and type 2 diabetes, obesity and atherosclerosis [37]. These correlate with macrophage metabolic and mitochondrial activities [38] and, possibly, ACE2 expression and hypertension, another co-morbidity [37]. ACE2, the COVID-19 entry receptor, is widely expressed on microvascular endothelium and binds the SARS-CoV2 spike glycoprotein implicated in angiotensin regulation by its competition with ACE1, and potential role as an anti-inflammatory agent [39]. Macrophages in tuberculosis and sarcoidosis express ACE1 [40], but expression of ACE2 by monocytes and tissue macrophages has not been validated [41]; evidence for productive infection of macrophages via ACE2 is incomplete [15]. Macrophages express scavenger receptors including Axl and MERTK, tyrosine kinase receptors implicated in phosphatidyl serine recognition and phagocytosis of apoptotic cells [21]; Axl is a coreceptor for ACE2+ dependent infection of other cell types by COVID-19 and other enveloped viruses via surface or endocytic routes [42], the basis for a clinical trial involving an Axl inhibitor.\nAlveolar macrophages [43] are close to Type 1 pneumocytes, involved in gas exchange, Type 2 surfactant-producing pneumocytes, and capillary endothelium, all ACE 2+ [43]. They take up and store atmospheric pollutants and poorly-degradable pro-inflammatory particles; host DNA from dying cells can induce the innate STING pathway after uptake and also activate inflammasomes in lung macrophages after exposure to ozone and cigarette smoke [31]. Other airway predisposing conditions involving macrophages [8,9], include genetic disorders such as fibrocystic disease and structural abnormalities associated with chronic inflammation and infection.\nChronic infections in which TH1-activated macrophages play a major role, tuberculosis and AIDS, enhance the risk of severe infection, with odds ratios of 1.7 and 2.3– respectively. TH2-dependent asthma may not enhance COVID-19 susceptibility, possibly correlated with low levels of ACE2 expression [44]. IL-13 also reduces ACE2 expression, suggesting that M2-macrophages may contribute to viral resistance. BCG and other immunisations may transiently promote non-specific resistance to SARS-CoV2 [45], to be confirmed in trials. Mononuclear phagocytes are implicated in selected genetic [46] or acquired systemic immunodeficiency, immunosuppression and autoimmunity, including chronic renal disease requiring organ transplantation. Tumor associated macrophages (TAM) and Myeloid derived suppressor cells (MDSC) promote malignancy and metastasis, and with chemo-and radiotherapy may enhance COVID-19 risk. Microglia contribute to neurodegeneration through interaction with neurons in Alzheimer disease, a comorbidity independent of age.\nComorbidities are likely to be multifactorial, and not all display an obvious macrophage link; for example, the ACE2 locus on the X chromosome [47] may contribute to the decreased risk of females [48], but genetic and environmental factors underlying gender, racial and individual disparities remain unclear. Therapeutics for many comorbidities impact on macrophage inflammatory and metabolic functions, including statins, sugar stabilizers, anti-hypertensives and anti-inflammatory agents; control of diabetes and obesity are important in preventing severe infection. Glucocorticoids, which have potent anti-inflammatory effects on macrophages, are contra-indicated in early infection, while protecting against severe disease; timing of administration is therefore critical [49]. The use of anti-TNF antibody in treatment of rheumatoid arthritis, protects against subsequent severe COVID-19 requiring hospitalization [50].\nIn conclusion, the present evidence for a common macrophage contribution to a range of comorbidities is correlative, rather than causal. Nor is it clear whether they increase the risk as well as the severity of infection. Macrophages are central to inflammation, immunity and metabolic diseases, but further genetic and cellular studies are needed to provide a unifying hypothesis.\n\n3.3 Asymptomatic and initial, mild infection\nThere is little direct evidence how monocytes and tissue macrophages contribute to asymptomatic infection, but their tissue distribution, receptor repertoire and secretory capacity are vital to viral resistance as well as dissemination. Acute macrophage antiviral and inflammatory responses determine the outcome of infection, together with other innate and adaptive host mechanisms. We outline evidence from clinical [20] and experimental observations from earlier [51] and current [20] coronavirus studies and consider the role of macrophages and monocytes in local and systemic infections, the antiviral and inflammatory response, resolution and complications.\nMost COVID-19 infections follow droplet inhalation and upper respiratory airway infection, which can be asymptomatic or mild, depending on mucosal immunity and IgA protection. Nasopharyngeal epithelium expresses ACE2 and is an early target for infection. Even if local tissue macrophages do not express ACE2 receptors and are not directly infected, they play a role in inflammatory cytokine responses to infected cells through surface, endosomal and cytosolic receptors and secretion of IL-1 family members [52] and antiviral interferons (IFNs). Monocytes, dendritic cells and tissue macrophages can bind virus through lectin-like receptors such as CD169 [53], for transport to regional lymph nodes. Delivery of virus droplets to the lower respiratory tract leads to infection of ACE2+ alveolar epithelium and capillary endothelium. Detection of intracellular RNA in alveolar macrophages could result from uptake of infected epithelial and endothelial cell debris rather than active infection. Single cell mRNA studies of bronchoalveolar lavage in COVID-19, have confirmed the recruitment of inflammatory monocytes as well as the presence of reactive alveolar macrophages in lung [17,18].\nSeveral common symptoms of early infection can be the indirect result of epithelial cell necrosis by viral infection mediated by ACE2 and/or other co-receptors, such as transmembrane protease serine 2, (TMPRSS2) [13]. Uptake of virus or epithelial cell debris by lung macrophages can initiate inflammasome activation by P2RX7 and release IL-1β, Type1 IFN, IL-6 and TNF [3], contributing to fever, pain, lethargy and headache. Raised levels of C-reactive protein (CRP), induced in hepatocytes by IL-6, are acute phase, plasma biomarkers of COVID-19. Other macrophage products include chemokines such as IL-8 (CXCL8) and MCP-1 (CCL2), recruiting abundant PMN and monocytes to sites of infection. Through viraemia COVID-19 reaches systemic organs such as heart, gut, brain and kidney, which contain resident and recruited macrophage populations; these contribute to local, specialised dysfunctions, such as myocarditis and cardiac arrhythmia, following interactions of macrophages and infected cardiomyocytes [54]. Intravascular coagulation [3,24] promotes dissemination of microthrombi-emboli to lungs, heart and brain, and fibrin degradation d-dimers appear in blood. This is evidence of early resolution, enhanced by the generation of antiviral IgM and IgG.\nWe have little understanding of the innate and adaptive mechanisms that fail to clear local viral infection and at what stage IFN [55,56], other pro-inflammatory [57] and haematopoietic responses become dysregulated in blood monocytes [58]. Together with compromised lung oxygenation, this can lead to systemic immune and vascular dysfunctions. A syndrome of mild infection in younger subjects gives rise to chilblain-like inflammation in toes and fingers [59]. The uncommon multisystem Kawasaki-like inflammatory syndrome of children results from atypical immune responses to COVID-19 [60,61]. This involves anti-viral antibody, systemic vasculitis affecting heart rather than lung, and can respond to corticosteroids. Apart from platelet activation, mononuclear phagocytes are known to produce tissue factor and other procoagulants [62], Factors 5 and 13; fibrinolysis by vascular endothelium and inflammatory macrophages [63] is mediated by secretion of urokinase, which cleaves plasminogen to plasmin; its activity is regulated by inhibitors in plasma, such as alpha2 macroglobulin. Anticoagulants and intranasal or inhaled Type1 IFN may be useful inhibitors of thrombosis and local viral infection, limiting progression to more severe infection.\n\n3.4 Moderate and severe infection: the hyperinflammatory syndrome\nBetween 8–12 days after COVID-19 infection, patients can progress to severe lung infection characterized by pneumonia, increased vascular permeability, edema, and hypoxia, requiring oxygen or mechanical ventilation. This is part of a systemic viral infection of ACE2+epithelia and endothelia, widespread cell death, ischaemia, hypotension and organ failure. Blood analysis at time of hospitalization, has revealed polymorphonuclear leukocytosis, altered levels of abnormal monocytes and lymphopaenia [58,64]. Myeloid cell recruitment to lung contributes to the hyperinflammatory and coagulopathy acute respiratory distress syndrome (ARDS) [20]. This is accompanied by monocyte/macrophage dysregulated production of secretory products. It is not clear which factors contribute to this complication: enhanced viral growth–perhaps triggered by early, poorly neutralizing IgM and complement or IgG, hypoxia and loss of antiviral mechanisms of macrophages–directly or secondary to lymphopaenia, massive local epithelial and endothelial necrosis, hyperactivation of newly recruited immature monocytes, or a “perfect storm” encompassing several of the above. This syndrome could be triggered by induction of ACE2 on specific populations of monocytes and macrophages, resulting in their direct infection. By this stage, spleen and draining nodes at sites of infection are severely disorganized [65]. M1-like monocytes carrying virus through CD169 or other receptors, whether infected or not, can disseminate the virus throughout the body by a Trojan horse mechanism [66]. It is not known whether lymphocytes, not infected, die by apoptosis or necrosis, from products of activated lymphocytes or macrophages such as TNF, or by phagoptosis. We summarize evidence that blood monocytes and activated tissue macrophages contribute to severe COVID-19 and consider virus-induced macrophage pathogenetic mechanisms, which can be targeted therapeutically.\nEarlier studies on SARS1/MERS revealed many of the features of ARDS and of macrophage involvement [6,51]. Initial blood and tissue analysis of COVID-19 provided morphologic evidence of monocyte abnormality and intense macrophage phagocytic activity in infected organs [65]. FACS and single cell RNA analysis of monocytes and broncho-alveolar macrophages [18] provided evidence of emergency myelopoiesis [64] and confirmed the presence of recruited and activated macrophages in alveoli [17] and lung interstitium. Plasma membrane opsonic and other receptors contribute to dysregulated inflammation, monocytic hyperactivation and impaired phagocytic clearance of apoptotic and necrotic cells and debris. Acting through NFkB, RNA, DNA and other sensing and signaling pathways, they initiate production of numerous secretory products. Particular antiviral and proinflammatory products have been targeted for anti-inflammatory treatment, including the IFNs [55,56], IL-1 family [52], IL-6 [27] and TNF [22]. In addition, mononuclear phagocytes interact with plasma cascades, and through upregulated adhesion molecules, with other myeloid and lymphoid cells, platelets, system-wide endothelia and epithelia.\nDysregulated activation of macrophages contributes to the hyperinflammatory and thrombotic pathways of severe COVID-19 [3,24,67].Virus-induced cell injury, apoptosis, necrosis and necroptosis are sensed by distinct, opposing macrophage receptor-dependent effector responses. These include activating and inhibitory pathways of IL-1 production, processing and secretion [52,57], triggered by tissue injury, inflammasome and caspase activation. A highly impaired type1 IFN response, characterized by no IFNβ and low IFNα production and activity, has been associated with persistent viraemia and an exacerbated inflammatory response, partially driven by NFkB, TNF and IL-6 [56]. Endogenous oxidized phospholipids reprogramme macrophage metabolism and boost hyperinflammation [68]. By capturing inflammatory lipids released from dying cells, CD14 induces inflammasome-dependent phagocyte hyperactivation [69]. Macrophage fuel production and utilization [36] are sensitive to hypoxia, HIF-1 responses [70] and iron availability, influencing M1 polarization and effector functions. Activated macrophages trigger coagulation and complement cascades, as well as angiotensin and bradykinin pathways that dysregulate vascular tone and permeability, exacerbating inflammation and edema.\nImmunological processes that may contribute to the outcome of macrophage- viral induced pathology include antibody enhancement of infection (ADE) and inflammation (ADI), and neutrophil NETosis. Anti-spike antiserum can induce hyperinflammation via macrophage FcR, depending on IgG glycosylation and Syk involvement [71]. Cross-reacting antibodies from previous benign coronavirus infections also contribute to enhanced pathology [72]. Dendritic cell dysfunction, ascribed to down regulated HLA-DR expression [67,72] and defective antigen presentation to T and B lymphocytes, may result from lack of costimulatory signals, aborting lymphocyte proliferation and activation and mediating widespread clonal death. Haemophagocytosis, a feature of the macrophage activation syndrome (MAS), is also observed in other viral infections.\n\n3.5 Recovery\nMacrophages are central to the cellular processes which contribute to recovery from COVID-19 infection; they remove debris and necrotic tissue through phagocytosis and secretion of elastase and collagenase, and produce IGF1 and TGF-β to promote tissue recovery. M2-like macrophages are the source of potent lipid metabolites which resolve inflammation; these include resolvins, protectins and maresins, short lived autacoids which regulate the magnitude and duration of acute inflammation [25,73]. Acting through macrophage GPCRs for these metabolites, they enhance efferocytosis of dying neutrophils, and counter inflammation without immunosuppression.\nRecovery can be prolonged after severe infection, involving fever, lethargy, scarring and loss of organ function. Italiani and colleagues profiled the course of resolving versus persistent inflammation with special reference to IL-1 family molecules [57]. An independent single cell mRNA analysis of peripheral blood mononuclear cells during early recovery of COVID-19 infection [23], revealed an increased ratio and level of classical CD14++IL-1β+ monocytes. Further studies are needed to compare monocytes and tissue macrophages after mild or severe infection and to establish whether repolarisation of macrophages from M1 to an M2 phenotype can promote resolution and recovery after COVID-19. After helminth infection, M2 macrophages express resistin, which protects against LPS-induced toxic shock [74]. New or repurposed therapies may be able to modify the sequelae of severe infection."}

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COVID-19 infection\n3.1 It is customary to divide the course of the infection into different stages: Preinfection (co-morbidities), asymptomatic, early clinical, severe clinical (acute respiratory distress syndrome–ARDS), and recovery [8,9], Fig. 2 . This natural timing should be used to establish key point-of-care sampling timepoints, avoiding patient discomfort and to focus resources. Infection can progress or be aborted at every stage, presenting a dynamic continuum, to which macrophages and monocytes contribute, together with other immune and non-immune elements; MPS contributions to COVID-19 resistance and pathogenesis are still underestimated and poorly understood.\nFig. 2 Decision points that determine the outcome of COVID-19 infection and requirements for a monocyte activation assay. A time and severity pattern has emerged for COVID-19 progression. The first days, first and second week timelines are turning points for resolution or deterioration. Epidemiologic precision for these milestones and precise parameters will be valuable for strategic sampling and patient stratification, sparing resources and patient material. With limited volumes of peripheral blood, a window on progression of the infection can be obtained by studying activation of the mononuclear phagocyte system, largely represented by monocytes in blood. The cells are biosynthetically active and relatively long lived, ideal to trace long term effects of comorbidities and infection. We highlight selected functional categories that should be addressed in monocytes and can be adapted to particular applications.\n\n3.2 Co-morbidities and the mps\nMacrophage activities contribute to many co- morbidities [8,9], including aging [28], obesity [29], diabetes [30], exposure to pollutants [31], and microbiome properties [32]. Macrophage functions alter with age, together with adaptive immune processes such as thymic involution, which deplete T lymphocyte reserves. Chronic, low grade inflammation (INFLAMMAGING) has been proposed as a predisposing factor [33]. This may result from failure of macrophages and NK cells to clear increasing accumulation of senescent cells, that enhance basal levels of inflammation and interfere with subsequent adaptive immunity upon infection [28]. Baseline inflammation may not be detrimental in itself, but can initiate an inflammatory cascade that amplifies excessive inflammation occurring in response to pathogens. Age-related metabolic correlates of macrophage dysfunction include innate lymphoid cell interactions with adipose tissue and associated macrophages, as well as inflammasome activation [34,35]. This affects thermogenesis, part of a wider metabolic syndrome involving glucose and lipid metabolism [36], elevated body mass index (BMI), type 1 and type 2 diabetes, obesity and atherosclerosis [37]. These correlate with macrophage metabolic and mitochondrial activities [38] and, possibly, ACE2 expression and hypertension, another co-morbidity [37]. ACE2, the COVID-19 entry receptor, is widely expressed on microvascular endothelium and binds the SARS-CoV2 spike glycoprotein implicated in angiotensin regulation by its competition with ACE1, and potential role as an anti-inflammatory agent [39]. Macrophages in tuberculosis and sarcoidosis express ACE1 [40], but expression of ACE2 by monocytes and tissue macrophages has not been validated [41]; evidence for productive infection of macrophages via ACE2 is incomplete [15]. Macrophages express scavenger receptors including Axl and MERTK, tyrosine kinase receptors implicated in phosphatidyl serine recognition and phagocytosis of apoptotic cells [21]; Axl is a coreceptor for ACE2+ dependent infection of other cell types by COVID-19 and other enveloped viruses via surface or endocytic routes [42], the basis for a clinical trial involving an Axl inhibitor.\nAlveolar macrophages [43] are close to Type 1 pneumocytes, involved in gas exchange, Type 2 surfactant-producing pneumocytes, and capillary endothelium, all ACE 2+ [43]. They take up and store atmospheric pollutants and poorly-degradable pro-inflammatory particles; host DNA from dying cells can induce the innate STING pathway after uptake and also activate inflammasomes in lung macrophages after exposure to ozone and cigarette smoke [31]. Other airway predisposing conditions involving macrophages [8,9], include genetic disorders such as fibrocystic disease and structural abnormalities associated with chronic inflammation and infection.\nChronic infections in which TH1-activated macrophages play a major role, tuberculosis and AIDS, enhance the risk of severe infection, with odds ratios of 1.7 and 2.3– respectively. TH2-dependent asthma may not enhance COVID-19 susceptibility, possibly correlated with low levels of ACE2 expression [44]. IL-13 also reduces ACE2 expression, suggesting that M2-macrophages may contribute to viral resistance. BCG and other immunisations may transiently promote non-specific resistance to SARS-CoV2 [45], to be confirmed in trials. Mononuclear phagocytes are implicated in selected genetic [46] or acquired systemic immunodeficiency, immunosuppression and autoimmunity, including chronic renal disease requiring organ transplantation. Tumor associated macrophages (TAM) and Myeloid derived suppressor cells (MDSC) promote malignancy and metastasis, and with chemo-and radiotherapy may enhance COVID-19 risk. Microglia contribute to neurodegeneration through interaction with neurons in Alzheimer disease, a comorbidity independent of age.\nComorbidities are likely to be multifactorial, and not all display an obvious macrophage link; for example, the ACE2 locus on the X chromosome [47] may contribute to the decreased risk of females [48], but genetic and environmental factors underlying gender, racial and individual disparities remain unclear. Therapeutics for many comorbidities impact on macrophage inflammatory and metabolic functions, including statins, sugar stabilizers, anti-hypertensives and anti-inflammatory agents; control of diabetes and obesity are important in preventing severe infection. Glucocorticoids, which have potent anti-inflammatory effects on macrophages, are contra-indicated in early infection, while protecting against severe disease; timing of administration is therefore critical [49]. The use of anti-TNF antibody in treatment of rheumatoid arthritis, protects against subsequent severe COVID-19 requiring hospitalization [50].\nIn conclusion, the present evidence for a common macrophage contribution to a range of comorbidities is correlative, rather than causal. Nor is it clear whether they increase the risk as well as the severity of infection. Macrophages are central to inflammation, immunity and metabolic diseases, but further genetic and cellular studies are needed to provide a unifying hypothesis.\n\n3.3 Asymptomatic and initial, mild infection\nThere is little direct evidence how monocytes and tissue macrophages contribute to asymptomatic infection, but their tissue distribution, receptor repertoire and secretory capacity are vital to viral resistance as well as dissemination. Acute macrophage antiviral and inflammatory responses determine the outcome of infection, together with other innate and adaptive host mechanisms. We outline evidence from clinical [20] and experimental observations from earlier [51] and current [20] coronavirus studies and consider the role of macrophages and monocytes in local and systemic infections, the antiviral and inflammatory response, resolution and complications.\nMost COVID-19 infections follow droplet inhalation and upper respiratory airway infection, which can be asymptomatic or mild, depending on mucosal immunity and IgA protection. Nasopharyngeal epithelium expresses ACE2 and is an early target for infection. Even if local tissue macrophages do not express ACE2 receptors and are not directly infected, they play a role in inflammatory cytokine responses to infected cells through surface, endosomal and cytosolic receptors and secretion of IL-1 family members [52] and antiviral interferons (IFNs). Monocytes, dendritic cells and tissue macrophages can bind virus through lectin-like receptors such as CD169 [53], for transport to regional lymph nodes. Delivery of virus droplets to the lower respiratory tract leads to infection of ACE2+ alveolar epithelium and capillary endothelium. Detection of intracellular RNA in alveolar macrophages could result from uptake of infected epithelial and endothelial cell debris rather than active infection. Single cell mRNA studies of bronchoalveolar lavage in COVID-19, have confirmed the recruitment of inflammatory monocytes as well as the presence of reactive alveolar macrophages in lung [17,18].\nSeveral common symptoms of early infection can be the indirect result of epithelial cell necrosis by viral infection mediated by ACE2 and/or other co-receptors, such as transmembrane protease serine 2, (TMPRSS2) [13]. Uptake of virus or epithelial cell debris by lung macrophages can initiate inflammasome activation by P2RX7 and release IL-1β, Type1 IFN, IL-6 and TNF [3], contributing to fever, pain, lethargy and headache. Raised levels of C-reactive protein (CRP), induced in hepatocytes by IL-6, are acute phase, plasma biomarkers of COVID-19. Other macrophage products include chemokines such as IL-8 (CXCL8) and MCP-1 (CCL2), recruiting abundant PMN and monocytes to sites of infection. Through viraemia COVID-19 reaches systemic organs such as heart, gut, brain and kidney, which contain resident and recruited macrophage populations; these contribute to local, specialised dysfunctions, such as myocarditis and cardiac arrhythmia, following interactions of macrophages and infected cardiomyocytes [54]. Intravascular coagulation [3,24] promotes dissemination of microthrombi-emboli to lungs, heart and brain, and fibrin degradation d-dimers appear in blood. This is evidence of early resolution, enhanced by the generation of antiviral IgM and IgG.\nWe have little understanding of the innate and adaptive mechanisms that fail to clear local viral infection and at what stage IFN [55,56], other pro-inflammatory [57] and haematopoietic responses become dysregulated in blood monocytes [58]. Together with compromised lung oxygenation, this can lead to systemic immune and vascular dysfunctions. A syndrome of mild infection in younger subjects gives rise to chilblain-like inflammation in toes and fingers [59]. The uncommon multisystem Kawasaki-like inflammatory syndrome of children results from atypical immune responses to COVID-19 [60,61]. This involves anti-viral antibody, systemic vasculitis affecting heart rather than lung, and can respond to corticosteroids. Apart from platelet activation, mononuclear phagocytes are known to produce tissue factor and other procoagulants [62], Factors 5 and 13; fibrinolysis by vascular endothelium and inflammatory macrophages [63] is mediated by secretion of urokinase, which cleaves plasminogen to plasmin; its activity is regulated by inhibitors in plasma, such as alpha2 macroglobulin. Anticoagulants and intranasal or inhaled Type1 IFN may be useful inhibitors of thrombosis and local viral infection, limiting progression to more severe infection.\n\n3.4 Moderate and severe infection: the hyperinflammatory syndrome\nBetween 8–12 days after COVID-19 infection, patients can progress to severe lung infection characterized by pneumonia, increased vascular permeability, edema, and hypoxia, requiring oxygen or mechanical ventilation. This is part of a systemic viral infection of ACE2+epithelia and endothelia, widespread cell death, ischaemia, hypotension and organ failure. Blood analysis at time of hospitalization, has revealed polymorphonuclear leukocytosis, altered levels of abnormal monocytes and lymphopaenia [58,64]. Myeloid cell recruitment to lung contributes to the hyperinflammatory and coagulopathy acute respiratory distress syndrome (ARDS) [20]. This is accompanied by monocyte/macrophage dysregulated production of secretory products. It is not clear which factors contribute to this complication: enhanced viral growth–perhaps triggered by early, poorly neutralizing IgM and complement or IgG, hypoxia and loss of antiviral mechanisms of macrophages–directly or secondary to lymphopaenia, massive local epithelial and endothelial necrosis, hyperactivation of newly recruited immature monocytes, or a “perfect storm” encompassing several of the above. This syndrome could be triggered by induction of ACE2 on specific populations of monocytes and macrophages, resulting in their direct infection. By this stage, spleen and draining nodes at sites of infection are severely disorganized [65]. M1-like monocytes carrying virus through CD169 or other receptors, whether infected or not, can disseminate the virus throughout the body by a Trojan horse mechanism [66]. It is not known whether lymphocytes, not infected, die by apoptosis or necrosis, from products of activated lymphocytes or macrophages such as TNF, or by phagoptosis. We summarize evidence that blood monocytes and activated tissue macrophages contribute to severe COVID-19 and consider virus-induced macrophage pathogenetic mechanisms, which can be targeted therapeutically.\nEarlier studies on SARS1/MERS revealed many of the features of ARDS and of macrophage involvement [6,51]. Initial blood and tissue analysis of COVID-19 provided morphologic evidence of monocyte abnormality and intense macrophage phagocytic activity in infected organs [65]. FACS and single cell RNA analysis of monocytes and broncho-alveolar macrophages [18] provided evidence of emergency myelopoiesis [64] and confirmed the presence of recruited and activated macrophages in alveoli [17] and lung interstitium. Plasma membrane opsonic and other receptors contribute to dysregulated inflammation, monocytic hyperactivation and impaired phagocytic clearance of apoptotic and necrotic cells and debris. Acting through NFkB, RNA, DNA and other sensing and signaling pathways, they initiate production of numerous secretory products. Particular antiviral and proinflammatory products have been targeted for anti-inflammatory treatment, including the IFNs [55,56], IL-1 family [52], IL-6 [27] and TNF [22]. In addition, mononuclear phagocytes interact with plasma cascades, and through upregulated adhesion molecules, with other myeloid and lymphoid cells, platelets, system-wide endothelia and epithelia.\nDysregulated activation of macrophages contributes to the hyperinflammatory and thrombotic pathways of severe COVID-19 [3,24,67].Virus-induced cell injury, apoptosis, necrosis and necroptosis are sensed by distinct, opposing macrophage receptor-dependent effector responses. These include activating and inhibitory pathways of IL-1 production, processing and secretion [52,57], triggered by tissue injury, inflammasome and caspase activation. A highly impaired type1 IFN response, characterized by no IFNβ and low IFNα production and activity, has been associated with persistent viraemia and an exacerbated inflammatory response, partially driven by NFkB, TNF and IL-6 [56]. Endogenous oxidized phospholipids reprogramme macrophage metabolism and boost hyperinflammation [68]. By capturing inflammatory lipids released from dying cells, CD14 induces inflammasome-dependent phagocyte hyperactivation [69]. Macrophage fuel production and utilization [36] are sensitive to hypoxia, HIF-1 responses [70] and iron availability, influencing M1 polarization and effector functions. Activated macrophages trigger coagulation and complement cascades, as well as angiotensin and bradykinin pathways that dysregulate vascular tone and permeability, exacerbating inflammation and edema.\nImmunological processes that may contribute to the outcome of macrophage- viral induced pathology include antibody enhancement of infection (ADE) and inflammation (ADI), and neutrophil NETosis. Anti-spike antiserum can induce hyperinflammation via macrophage FcR, depending on IgG glycosylation and Syk involvement [71]. Cross-reacting antibodies from previous benign coronavirus infections also contribute to enhanced pathology [72]. Dendritic cell dysfunction, ascribed to down regulated HLA-DR expression [67,72] and defective antigen presentation to T and B lymphocytes, may result from lack of costimulatory signals, aborting lymphocyte proliferation and activation and mediating widespread clonal death. Haemophagocytosis, a feature of the macrophage activation syndrome (MAS), is also observed in other viral infections.\n\n3.5 Recovery\nMacrophages are central to the cellular processes which contribute to recovery from COVID-19 infection; they remove debris and necrotic tissue through phagocytosis and secretion of elastase and collagenase, and produce IGF1 and TGF-β to promote tissue recovery. M2-like macrophages are the source of potent lipid metabolites which resolve inflammation; these include resolvins, protectins and maresins, short lived autacoids which regulate the magnitude and duration of acute inflammation [25,73]. Acting through macrophage GPCRs for these metabolites, they enhance efferocytosis of dying neutrophils, and counter inflammation without immunosuppression.\nRecovery can be prolonged after severe infection, involving fever, lethargy, scarring and loss of organ function. Italiani and colleagues profiled the course of resolving versus persistent inflammation with special reference to IL-1 family molecules [57]. An independent single cell mRNA analysis of peripheral blood mononuclear cells during early recovery of COVID-19 infection [23], revealed an increased ratio and level of classical CD14++IL-1β+ monocytes. Further studies are needed to compare monocytes and tissue macrophages after mild or severe infection and to establish whether repolarisation of macrophages from M1 to an M2 phenotype can promote resolution and recovery after COVID-19. After helminth infection, M2 macrophages express resistin, which protects against LPS-induced toxic shock [74]. New or repurposed therapies may be able to modify the sequelae of severe infection."}

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COVID-19 infection\n3.1 It is customary to divide the course of the infection into different stages: Preinfection (co-morbidities), asymptomatic, early clinical, severe clinical (acute respiratory distress syndrome–ARDS), and recovery [8,9], Fig. 2 . This natural timing should be used to establish key point-of-care sampling timepoints, avoiding patient discomfort and to focus resources. Infection can progress or be aborted at every stage, presenting a dynamic continuum, to which macrophages and monocytes contribute, together with other immune and non-immune elements; MPS contributions to COVID-19 resistance and pathogenesis are still underestimated and poorly understood.\nFig. 2 Decision points that determine the outcome of COVID-19 infection and requirements for a monocyte activation assay. A time and severity pattern has emerged for COVID-19 progression. The first days, first and second week timelines are turning points for resolution or deterioration. Epidemiologic precision for these milestones and precise parameters will be valuable for strategic sampling and patient stratification, sparing resources and patient material. With limited volumes of peripheral blood, a window on progression of the infection can be obtained by studying activation of the mononuclear phagocyte system, largely represented by monocytes in blood. The cells are biosynthetically active and relatively long lived, ideal to trace long term effects of comorbidities and infection. We highlight selected functional categories that should be addressed in monocytes and can be adapted to particular applications.\n\n3.2 Co-morbidities and the mps\nMacrophage activities contribute to many co- morbidities [8,9], including aging [28], obesity [29], diabetes [30], exposure to pollutants [31], and microbiome properties [32]. Macrophage functions alter with age, together with adaptive immune processes such as thymic involution, which deplete T lymphocyte reserves. Chronic, low grade inflammation (INFLAMMAGING) has been proposed as a predisposing factor [33]. This may result from failure of macrophages and NK cells to clear increasing accumulation of senescent cells, that enhance basal levels of inflammation and interfere with subsequent adaptive immunity upon infection [28]. Baseline inflammation may not be detrimental in itself, but can initiate an inflammatory cascade that amplifies excessive inflammation occurring in response to pathogens. Age-related metabolic correlates of macrophage dysfunction include innate lymphoid cell interactions with adipose tissue and associated macrophages, as well as inflammasome activation [34,35]. This affects thermogenesis, part of a wider metabolic syndrome involving glucose and lipid metabolism [36], elevated body mass index (BMI), type 1 and type 2 diabetes, obesity and atherosclerosis [37]. These correlate with macrophage metabolic and mitochondrial activities [38] and, possibly, ACE2 expression and hypertension, another co-morbidity [37]. ACE2, the COVID-19 entry receptor, is widely expressed on microvascular endothelium and binds the SARS-CoV2 spike glycoprotein implicated in angiotensin regulation by its competition with ACE1, and potential role as an anti-inflammatory agent [39]. Macrophages in tuberculosis and sarcoidosis express ACE1 [40], but expression of ACE2 by monocytes and tissue macrophages has not been validated [41]; evidence for productive infection of macrophages via ACE2 is incomplete [15]. Macrophages express scavenger receptors including Axl and MERTK, tyrosine kinase receptors implicated in phosphatidyl serine recognition and phagocytosis of apoptotic cells [21]; Axl is a coreceptor for ACE2+ dependent infection of other cell types by COVID-19 and other enveloped viruses via surface or endocytic routes [42], the basis for a clinical trial involving an Axl inhibitor.\nAlveolar macrophages [43] are close to Type 1 pneumocytes, involved in gas exchange, Type 2 surfactant-producing pneumocytes, and capillary endothelium, all ACE 2+ [43]. They take up and store atmospheric pollutants and poorly-degradable pro-inflammatory particles; host DNA from dying cells can induce the innate STING pathway after uptake and also activate inflammasomes in lung macrophages after exposure to ozone and cigarette smoke [31]. Other airway predisposing conditions involving macrophages [8,9], include genetic disorders such as fibrocystic disease and structural abnormalities associated with chronic inflammation and infection.\nChronic infections in which TH1-activated macrophages play a major role, tuberculosis and AIDS, enhance the risk of severe infection, with odds ratios of 1.7 and 2.3– respectively. TH2-dependent asthma may not enhance COVID-19 susceptibility, possibly correlated with low levels of ACE2 expression [44]. IL-13 also reduces ACE2 expression, suggesting that M2-macrophages may contribute to viral resistance. BCG and other immunisations may transiently promote non-specific resistance to SARS-CoV2 [45], to be confirmed in trials. Mononuclear phagocytes are implicated in selected genetic [46] or acquired systemic immunodeficiency, immunosuppression and autoimmunity, including chronic renal disease requiring organ transplantation. Tumor associated macrophages (TAM) and Myeloid derived suppressor cells (MDSC) promote malignancy and metastasis, and with chemo-and radiotherapy may enhance COVID-19 risk. Microglia contribute to neurodegeneration through interaction with neurons in Alzheimer disease, a comorbidity independent of age.\nComorbidities are likely to be multifactorial, and not all display an obvious macrophage link; for example, the ACE2 locus on the X chromosome [47] may contribute to the decreased risk of females [48], but genetic and environmental factors underlying gender, racial and individual disparities remain unclear. Therapeutics for many comorbidities impact on macrophage inflammatory and metabolic functions, including statins, sugar stabilizers, anti-hypertensives and anti-inflammatory agents; control of diabetes and obesity are important in preventing severe infection. Glucocorticoids, which have potent anti-inflammatory effects on macrophages, are contra-indicated in early infection, while protecting against severe disease; timing of administration is therefore critical [49]. The use of anti-TNF antibody in treatment of rheumatoid arthritis, protects against subsequent severe COVID-19 requiring hospitalization [50].\nIn conclusion, the present evidence for a common macrophage contribution to a range of comorbidities is correlative, rather than causal. Nor is it clear whether they increase the risk as well as the severity of infection. Macrophages are central to inflammation, immunity and metabolic diseases, but further genetic and cellular studies are needed to provide a unifying hypothesis.\n\n3.3 Asymptomatic and initial, mild infection\nThere is little direct evidence how monocytes and tissue macrophages contribute to asymptomatic infection, but their tissue distribution, receptor repertoire and secretory capacity are vital to viral resistance as well as dissemination. Acute macrophage antiviral and inflammatory responses determine the outcome of infection, together with other innate and adaptive host mechanisms. We outline evidence from clinical [20] and experimental observations from earlier [51] and current [20] coronavirus studies and consider the role of macrophages and monocytes in local and systemic infections, the antiviral and inflammatory response, resolution and complications.\nMost COVID-19 infections follow droplet inhalation and upper respiratory airway infection, which can be asymptomatic or mild, depending on mucosal immunity and IgA protection. Nasopharyngeal epithelium expresses ACE2 and is an early target for infection. Even if local tissue macrophages do not express ACE2 receptors and are not directly infected, they play a role in inflammatory cytokine responses to infected cells through surface, endosomal and cytosolic receptors and secretion of IL-1 family members [52] and antiviral interferons (IFNs). Monocytes, dendritic cells and tissue macrophages can bind virus through lectin-like receptors such as CD169 [53], for transport to regional lymph nodes. Delivery of virus droplets to the lower respiratory tract leads to infection of ACE2+ alveolar epithelium and capillary endothelium. Detection of intracellular RNA in alveolar macrophages could result from uptake of infected epithelial and endothelial cell debris rather than active infection. Single cell mRNA studies of bronchoalveolar lavage in COVID-19, have confirmed the recruitment of inflammatory monocytes as well as the presence of reactive alveolar macrophages in lung [17,18].\nSeveral common symptoms of early infection can be the indirect result of epithelial cell necrosis by viral infection mediated by ACE2 and/or other co-receptors, such as transmembrane protease serine 2, (TMPRSS2) [13]. Uptake of virus or epithelial cell debris by lung macrophages can initiate inflammasome activation by P2RX7 and release IL-1β, Type1 IFN, IL-6 and TNF [3], contributing to fever, pain, lethargy and headache. Raised levels of C-reactive protein (CRP), induced in hepatocytes by IL-6, are acute phase, plasma biomarkers of COVID-19. Other macrophage products include chemokines such as IL-8 (CXCL8) and MCP-1 (CCL2), recruiting abundant PMN and monocytes to sites of infection. Through viraemia COVID-19 reaches systemic organs such as heart, gut, brain and kidney, which contain resident and recruited macrophage populations; these contribute to local, specialised dysfunctions, such as myocarditis and cardiac arrhythmia, following interactions of macrophages and infected cardiomyocytes [54]. Intravascular coagulation [3,24] promotes dissemination of microthrombi-emboli to lungs, heart and brain, and fibrin degradation d-dimers appear in blood. This is evidence of early resolution, enhanced by the generation of antiviral IgM and IgG.\nWe have little understanding of the innate and adaptive mechanisms that fail to clear local viral infection and at what stage IFN [55,56], other pro-inflammatory [57] and haematopoietic responses become dysregulated in blood monocytes [58]. Together with compromised lung oxygenation, this can lead to systemic immune and vascular dysfunctions. A syndrome of mild infection in younger subjects gives rise to chilblain-like inflammation in toes and fingers [59]. The uncommon multisystem Kawasaki-like inflammatory syndrome of children results from atypical immune responses to COVID-19 [60,61]. This involves anti-viral antibody, systemic vasculitis affecting heart rather than lung, and can respond to corticosteroids. Apart from platelet activation, mononuclear phagocytes are known to produce tissue factor and other procoagulants [62], Factors 5 and 13; fibrinolysis by vascular endothelium and inflammatory macrophages [63] is mediated by secretion of urokinase, which cleaves plasminogen to plasmin; its activity is regulated by inhibitors in plasma, such as alpha2 macroglobulin. Anticoagulants and intranasal or inhaled Type1 IFN may be useful inhibitors of thrombosis and local viral infection, limiting progression to more severe infection.\n\n3.4 Moderate and severe infection: the hyperinflammatory syndrome\nBetween 8–12 days after COVID-19 infection, patients can progress to severe lung infection characterized by pneumonia, increased vascular permeability, edema, and hypoxia, requiring oxygen or mechanical ventilation. This is part of a systemic viral infection of ACE2+epithelia and endothelia, widespread cell death, ischaemia, hypotension and organ failure. Blood analysis at time of hospitalization, has revealed polymorphonuclear leukocytosis, altered levels of abnormal monocytes and lymphopaenia [58,64]. Myeloid cell recruitment to lung contributes to the hyperinflammatory and coagulopathy acute respiratory distress syndrome (ARDS) [20]. This is accompanied by monocyte/macrophage dysregulated production of secretory products. It is not clear which factors contribute to this complication: enhanced viral growth–perhaps triggered by early, poorly neutralizing IgM and complement or IgG, hypoxia and loss of antiviral mechanisms of macrophages–directly or secondary to lymphopaenia, massive local epithelial and endothelial necrosis, hyperactivation of newly recruited immature monocytes, or a “perfect storm” encompassing several of the above. This syndrome could be triggered by induction of ACE2 on specific populations of monocytes and macrophages, resulting in their direct infection. By this stage, spleen and draining nodes at sites of infection are severely disorganized [65]. M1-like monocytes carrying virus through CD169 or other receptors, whether infected or not, can disseminate the virus throughout the body by a Trojan horse mechanism [66]. It is not known whether lymphocytes, not infected, die by apoptosis or necrosis, from products of activated lymphocytes or macrophages such as TNF, or by phagoptosis. We summarize evidence that blood monocytes and activated tissue macrophages contribute to severe COVID-19 and consider virus-induced macrophage pathogenetic mechanisms, which can be targeted therapeutically.\nEarlier studies on SARS1/MERS revealed many of the features of ARDS and of macrophage involvement [6,51]. Initial blood and tissue analysis of COVID-19 provided morphologic evidence of monocyte abnormality and intense macrophage phagocytic activity in infected organs [65]. FACS and single cell RNA analysis of monocytes and broncho-alveolar macrophages [18] provided evidence of emergency myelopoiesis [64] and confirmed the presence of recruited and activated macrophages in alveoli [17] and lung interstitium. Plasma membrane opsonic and other receptors contribute to dysregulated inflammation, monocytic hyperactivation and impaired phagocytic clearance of apoptotic and necrotic cells and debris. Acting through NFkB, RNA, DNA and other sensing and signaling pathways, they initiate production of numerous secretory products. Particular antiviral and proinflammatory products have been targeted for anti-inflammatory treatment, including the IFNs [55,56], IL-1 family [52], IL-6 [27] and TNF [22]. In addition, mononuclear phagocytes interact with plasma cascades, and through upregulated adhesion molecules, with other myeloid and lymphoid cells, platelets, system-wide endothelia and epithelia.\nDysregulated activation of macrophages contributes to the hyperinflammatory and thrombotic pathways of severe COVID-19 [3,24,67].Virus-induced cell injury, apoptosis, necrosis and necroptosis are sensed by distinct, opposing macrophage receptor-dependent effector responses. These include activating and inhibitory pathways of IL-1 production, processing and secretion [52,57], triggered by tissue injury, inflammasome and caspase activation. A highly impaired type1 IFN response, characterized by no IFNβ and low IFNα production and activity, has been associated with persistent viraemia and an exacerbated inflammatory response, partially driven by NFkB, TNF and IL-6 [56]. Endogenous oxidized phospholipids reprogramme macrophage metabolism and boost hyperinflammation [68]. By capturing inflammatory lipids released from dying cells, CD14 induces inflammasome-dependent phagocyte hyperactivation [69]. Macrophage fuel production and utilization [36] are sensitive to hypoxia, HIF-1 responses [70] and iron availability, influencing M1 polarization and effector functions. Activated macrophages trigger coagulation and complement cascades, as well as angiotensin and bradykinin pathways that dysregulate vascular tone and permeability, exacerbating inflammation and edema.\nImmunological processes that may contribute to the outcome of macrophage- viral induced pathology include antibody enhancement of infection (ADE) and inflammation (ADI), and neutrophil NETosis. Anti-spike antiserum can induce hyperinflammation via macrophage FcR, depending on IgG glycosylation and Syk involvement [71]. Cross-reacting antibodies from previous benign coronavirus infections also contribute to enhanced pathology [72]. Dendritic cell dysfunction, ascribed to down regulated HLA-DR expression [67,72] and defective antigen presentation to T and B lymphocytes, may result from lack of costimulatory signals, aborting lymphocyte proliferation and activation and mediating widespread clonal death. Haemophagocytosis, a feature of the macrophage activation syndrome (MAS), is also observed in other viral infections.\n\n3.5 Recovery\nMacrophages are central to the cellular processes which contribute to recovery from COVID-19 infection; they remove debris and necrotic tissue through phagocytosis and secretion of elastase and collagenase, and produce IGF1 and TGF-β to promote tissue recovery. M2-like macrophages are the source of potent lipid metabolites which resolve inflammation; these include resolvins, protectins and maresins, short lived autacoids which regulate the magnitude and duration of acute inflammation [25,73]. Acting through macrophage GPCRs for these metabolites, they enhance efferocytosis of dying neutrophils, and counter inflammation without immunosuppression.\nRecovery can be prolonged after severe infection, involving fever, lethargy, scarring and loss of organ function. Italiani and colleagues profiled the course of resolving versus persistent inflammation with special reference to IL-1 family molecules [57]. An independent single cell mRNA analysis of peripheral blood mononuclear cells during early recovery of COVID-19 infection [23], revealed an increased ratio and level of classical CD14++IL-1β+ monocytes. Further studies are needed to compare monocytes and tissue macrophages after mild or severe infection and to establish whether repolarisation of macrophages from M1 to an M2 phenotype can promote resolution and recovery after COVID-19. After helminth infection, M2 macrophages express resistin, which protects against LPS-induced toxic shock [74]. New or repurposed therapies may be able to modify the sequelae of severe infection."}

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COVID-19 infection\n3.1 It is customary to divide the course of the infection into different stages: Preinfection (co-morbidities), asymptomatic, early clinical, severe clinical (acute respiratory distress syndrome–ARDS), and recovery [8,9], Fig. 2 . This natural timing should be used to establish key point-of-care sampling timepoints, avoiding patient discomfort and to focus resources. Infection can progress or be aborted at every stage, presenting a dynamic continuum, to which macrophages and monocytes contribute, together with other immune and non-immune elements; MPS contributions to COVID-19 resistance and pathogenesis are still underestimated and poorly understood.\nFig. 2 Decision points that determine the outcome of COVID-19 infection and requirements for a monocyte activation assay. A time and severity pattern has emerged for COVID-19 progression. The first days, first and second week timelines are turning points for resolution or deterioration. Epidemiologic precision for these milestones and precise parameters will be valuable for strategic sampling and patient stratification, sparing resources and patient material. With limited volumes of peripheral blood, a window on progression of the infection can be obtained by studying activation of the mononuclear phagocyte system, largely represented by monocytes in blood. The cells are biosynthetically active and relatively long lived, ideal to trace long term effects of comorbidities and infection. We highlight selected functional categories that should be addressed in monocytes and can be adapted to particular applications.\n\n3.2 Co-morbidities and the mps\nMacrophage activities contribute to many co- morbidities [8,9], including aging [28], obesity [29], diabetes [30], exposure to pollutants [31], and microbiome properties [32]. Macrophage functions alter with age, together with adaptive immune processes such as thymic involution, which deplete T lymphocyte reserves. Chronic, low grade inflammation (INFLAMMAGING) has been proposed as a predisposing factor [33]. This may result from failure of macrophages and NK cells to clear increasing accumulation of senescent cells, that enhance basal levels of inflammation and interfere with subsequent adaptive immunity upon infection [28]. Baseline inflammation may not be detrimental in itself, but can initiate an inflammatory cascade that amplifies excessive inflammation occurring in response to pathogens. Age-related metabolic correlates of macrophage dysfunction include innate lymphoid cell interactions with adipose tissue and associated macrophages, as well as inflammasome activation [34,35]. This affects thermogenesis, part of a wider metabolic syndrome involving glucose and lipid metabolism [36], elevated body mass index (BMI), type 1 and type 2 diabetes, obesity and atherosclerosis [37]. These correlate with macrophage metabolic and mitochondrial activities [38] and, possibly, ACE2 expression and hypertension, another co-morbidity [37]. ACE2, the COVID-19 entry receptor, is widely expressed on microvascular endothelium and binds the SARS-CoV2 spike glycoprotein implicated in angiotensin regulation by its competition with ACE1, and potential role as an anti-inflammatory agent [39]. Macrophages in tuberculosis and sarcoidosis express ACE1 [40], but expression of ACE2 by monocytes and tissue macrophages has not been validated [41]; evidence for productive infection of macrophages via ACE2 is incomplete [15]. Macrophages express scavenger receptors including Axl and MERTK, tyrosine kinase receptors implicated in phosphatidyl serine recognition and phagocytosis of apoptotic cells [21]; Axl is a coreceptor for ACE2+ dependent infection of other cell types by COVID-19 and other enveloped viruses via surface or endocytic routes [42], the basis for a clinical trial involving an Axl inhibitor.\nAlveolar macrophages [43] are close to Type 1 pneumocytes, involved in gas exchange, Type 2 surfactant-producing pneumocytes, and capillary endothelium, all ACE 2+ [43]. They take up and store atmospheric pollutants and poorly-degradable pro-inflammatory particles; host DNA from dying cells can induce the innate STING pathway after uptake and also activate inflammasomes in lung macrophages after exposure to ozone and cigarette smoke [31]. Other airway predisposing conditions involving macrophages [8,9], include genetic disorders such as fibrocystic disease and structural abnormalities associated with chronic inflammation and infection.\nChronic infections in which TH1-activated macrophages play a major role, tuberculosis and AIDS, enhance the risk of severe infection, with odds ratios of 1.7 and 2.3– respectively. TH2-dependent asthma may not enhance COVID-19 susceptibility, possibly correlated with low levels of ACE2 expression [44]. IL-13 also reduces ACE2 expression, suggesting that M2-macrophages may contribute to viral resistance. BCG and other immunisations may transiently promote non-specific resistance to SARS-CoV2 [45], to be confirmed in trials. Mononuclear phagocytes are implicated in selected genetic [46] or acquired systemic immunodeficiency, immunosuppression and autoimmunity, including chronic renal disease requiring organ transplantation. Tumor associated macrophages (TAM) and Myeloid derived suppressor cells (MDSC) promote malignancy and metastasis, and with chemo-and radiotherapy may enhance COVID-19 risk. Microglia contribute to neurodegeneration through interaction with neurons in Alzheimer disease, a comorbidity independent of age.\nComorbidities are likely to be multifactorial, and not all display an obvious macrophage link; for example, the ACE2 locus on the X chromosome [47] may contribute to the decreased risk of females [48], but genetic and environmental factors underlying gender, racial and individual disparities remain unclear. Therapeutics for many comorbidities impact on macrophage inflammatory and metabolic functions, including statins, sugar stabilizers, anti-hypertensives and anti-inflammatory agents; control of diabetes and obesity are important in preventing severe infection. Glucocorticoids, which have potent anti-inflammatory effects on macrophages, are contra-indicated in early infection, while protecting against severe disease; timing of administration is therefore critical [49]. The use of anti-TNF antibody in treatment of rheumatoid arthritis, protects against subsequent severe COVID-19 requiring hospitalization [50].\nIn conclusion, the present evidence for a common macrophage contribution to a range of comorbidities is correlative, rather than causal. Nor is it clear whether they increase the risk as well as the severity of infection. Macrophages are central to inflammation, immunity and metabolic diseases, but further genetic and cellular studies are needed to provide a unifying hypothesis.\n\n3.3 Asymptomatic and initial, mild infection\nThere is little direct evidence how monocytes and tissue macrophages contribute to asymptomatic infection, but their tissue distribution, receptor repertoire and secretory capacity are vital to viral resistance as well as dissemination. Acute macrophage antiviral and inflammatory responses determine the outcome of infection, together with other innate and adaptive host mechanisms. We outline evidence from clinical [20] and experimental observations from earlier [51] and current [20] coronavirus studies and consider the role of macrophages and monocytes in local and systemic infections, the antiviral and inflammatory response, resolution and complications.\nMost COVID-19 infections follow droplet inhalation and upper respiratory airway infection, which can be asymptomatic or mild, depending on mucosal immunity and IgA protection. Nasopharyngeal epithelium expresses ACE2 and is an early target for infection. Even if local tissue macrophages do not express ACE2 receptors and are not directly infected, they play a role in inflammatory cytokine responses to infected cells through surface, endosomal and cytosolic receptors and secretion of IL-1 family members [52] and antiviral interferons (IFNs). Monocytes, dendritic cells and tissue macrophages can bind virus through lectin-like receptors such as CD169 [53], for transport to regional lymph nodes. Delivery of virus droplets to the lower respiratory tract leads to infection of ACE2+ alveolar epithelium and capillary endothelium. Detection of intracellular RNA in alveolar macrophages could result from uptake of infected epithelial and endothelial cell debris rather than active infection. Single cell mRNA studies of bronchoalveolar lavage in COVID-19, have confirmed the recruitment of inflammatory monocytes as well as the presence of reactive alveolar macrophages in lung [17,18].\nSeveral common symptoms of early infection can be the indirect result of epithelial cell necrosis by viral infection mediated by ACE2 and/or other co-receptors, such as transmembrane protease serine 2, (TMPRSS2) [13]. Uptake of virus or epithelial cell debris by lung macrophages can initiate inflammasome activation by P2RX7 and release IL-1β, Type1 IFN, IL-6 and TNF [3], contributing to fever, pain, lethargy and headache. Raised levels of C-reactive protein (CRP), induced in hepatocytes by IL-6, are acute phase, plasma biomarkers of COVID-19. Other macrophage products include chemokines such as IL-8 (CXCL8) and MCP-1 (CCL2), recruiting abundant PMN and monocytes to sites of infection. Through viraemia COVID-19 reaches systemic organs such as heart, gut, brain and kidney, which contain resident and recruited macrophage populations; these contribute to local, specialised dysfunctions, such as myocarditis and cardiac arrhythmia, following interactions of macrophages and infected cardiomyocytes [54]. Intravascular coagulation [3,24] promotes dissemination of microthrombi-emboli to lungs, heart and brain, and fibrin degradation d-dimers appear in blood. This is evidence of early resolution, enhanced by the generation of antiviral IgM and IgG.\nWe have little understanding of the innate and adaptive mechanisms that fail to clear local viral infection and at what stage IFN [55,56], other pro-inflammatory [57] and haematopoietic responses become dysregulated in blood monocytes [58]. Together with compromised lung oxygenation, this can lead to systemic immune and vascular dysfunctions. A syndrome of mild infection in younger subjects gives rise to chilblain-like inflammation in toes and fingers [59]. The uncommon multisystem Kawasaki-like inflammatory syndrome of children results from atypical immune responses to COVID-19 [60,61]. This involves anti-viral antibody, systemic vasculitis affecting heart rather than lung, and can respond to corticosteroids. Apart from platelet activation, mononuclear phagocytes are known to produce tissue factor and other procoagulants [62], Factors 5 and 13; fibrinolysis by vascular endothelium and inflammatory macrophages [63] is mediated by secretion of urokinase, which cleaves plasminogen to plasmin; its activity is regulated by inhibitors in plasma, such as alpha2 macroglobulin. Anticoagulants and intranasal or inhaled Type1 IFN may be useful inhibitors of thrombosis and local viral infection, limiting progression to more severe infection.\n\n3.4 Moderate and severe infection: the hyperinflammatory syndrome\nBetween 8–12 days after COVID-19 infection, patients can progress to severe lung infection characterized by pneumonia, increased vascular permeability, edema, and hypoxia, requiring oxygen or mechanical ventilation. This is part of a systemic viral infection of ACE2+epithelia and endothelia, widespread cell death, ischaemia, hypotension and organ failure. Blood analysis at time of hospitalization, has revealed polymorphonuclear leukocytosis, altered levels of abnormal monocytes and lymphopaenia [58,64]. Myeloid cell recruitment to lung contributes to the hyperinflammatory and coagulopathy acute respiratory distress syndrome (ARDS) [20]. This is accompanied by monocyte/macrophage dysregulated production of secretory products. It is not clear which factors contribute to this complication: enhanced viral growth–perhaps triggered by early, poorly neutralizing IgM and complement or IgG, hypoxia and loss of antiviral mechanisms of macrophages–directly or secondary to lymphopaenia, massive local epithelial and endothelial necrosis, hyperactivation of newly recruited immature monocytes, or a “perfect storm” encompassing several of the above. This syndrome could be triggered by induction of ACE2 on specific populations of monocytes and macrophages, resulting in their direct infection. By this stage, spleen and draining nodes at sites of infection are severely disorganized [65]. M1-like monocytes carrying virus through CD169 or other receptors, whether infected or not, can disseminate the virus throughout the body by a Trojan horse mechanism [66]. It is not known whether lymphocytes, not infected, die by apoptosis or necrosis, from products of activated lymphocytes or macrophages such as TNF, or by phagoptosis. We summarize evidence that blood monocytes and activated tissue macrophages contribute to severe COVID-19 and consider virus-induced macrophage pathogenetic mechanisms, which can be targeted therapeutically.\nEarlier studies on SARS1/MERS revealed many of the features of ARDS and of macrophage involvement [6,51]. Initial blood and tissue analysis of COVID-19 provided morphologic evidence of monocyte abnormality and intense macrophage phagocytic activity in infected organs [65]. FACS and single cell RNA analysis of monocytes and broncho-alveolar macrophages [18] provided evidence of emergency myelopoiesis [64] and confirmed the presence of recruited and activated macrophages in alveoli [17] and lung interstitium. Plasma membrane opsonic and other receptors contribute to dysregulated inflammation, monocytic hyperactivation and impaired phagocytic clearance of apoptotic and necrotic cells and debris. Acting through NFkB, RNA, DNA and other sensing and signaling pathways, they initiate production of numerous secretory products. Particular antiviral and proinflammatory products have been targeted for anti-inflammatory treatment, including the IFNs [55,56], IL-1 family [52], IL-6 [27] and TNF [22]. In addition, mononuclear phagocytes interact with plasma cascades, and through upregulated adhesion molecules, with other myeloid and lymphoid cells, platelets, system-wide endothelia and epithelia.\nDysregulated activation of macrophages contributes to the hyperinflammatory and thrombotic pathways of severe COVID-19 [3,24,67].Virus-induced cell injury, apoptosis, necrosis and necroptosis are sensed by distinct, opposing macrophage receptor-dependent effector responses. These include activating and inhibitory pathways of IL-1 production, processing and secretion [52,57], triggered by tissue injury, inflammasome and caspase activation. A highly impaired type1 IFN response, characterized by no IFNβ and low IFNα production and activity, has been associated with persistent viraemia and an exacerbated inflammatory response, partially driven by NFkB, TNF and IL-6 [56]. Endogenous oxidized phospholipids reprogramme macrophage metabolism and boost hyperinflammation [68]. By capturing inflammatory lipids released from dying cells, CD14 induces inflammasome-dependent phagocyte hyperactivation [69]. Macrophage fuel production and utilization [36] are sensitive to hypoxia, HIF-1 responses [70] and iron availability, influencing M1 polarization and effector functions. Activated macrophages trigger coagulation and complement cascades, as well as angiotensin and bradykinin pathways that dysregulate vascular tone and permeability, exacerbating inflammation and edema.\nImmunological processes that may contribute to the outcome of macrophage- viral induced pathology include antibody enhancement of infection (ADE) and inflammation (ADI), and neutrophil NETosis. Anti-spike antiserum can induce hyperinflammation via macrophage FcR, depending on IgG glycosylation and Syk involvement [71]. Cross-reacting antibodies from previous benign coronavirus infections also contribute to enhanced pathology [72]. Dendritic cell dysfunction, ascribed to down regulated HLA-DR expression [67,72] and defective antigen presentation to T and B lymphocytes, may result from lack of costimulatory signals, aborting lymphocyte proliferation and activation and mediating widespread clonal death. Haemophagocytosis, a feature of the macrophage activation syndrome (MAS), is also observed in other viral infections.\n\n3.5 Recovery\nMacrophages are central to the cellular processes which contribute to recovery from COVID-19 infection; they remove debris and necrotic tissue through phagocytosis and secretion of elastase and collagenase, and produce IGF1 and TGF-β to promote tissue recovery. M2-like macrophages are the source of potent lipid metabolites which resolve inflammation; these include resolvins, protectins and maresins, short lived autacoids which regulate the magnitude and duration of acute inflammation [25,73]. Acting through macrophage GPCRs for these metabolites, they enhance efferocytosis of dying neutrophils, and counter inflammation without immunosuppression.\nRecovery can be prolonged after severe infection, involving fever, lethargy, scarring and loss of organ function. Italiani and colleagues profiled the course of resolving versus persistent inflammation with special reference to IL-1 family molecules [57]. An independent single cell mRNA analysis of peripheral blood mononuclear cells during early recovery of COVID-19 infection [23], revealed an increased ratio and level of classical CD14++IL-1β+ monocytes. Further studies are needed to compare monocytes and tissue macrophages after mild or severe infection and to establish whether repolarisation of macrophages from M1 to an M2 phenotype can promote resolution and recovery after COVID-19. After helminth infection, M2 macrophages express resistin, which protects against LPS-induced toxic shock [74]. New or repurposed therapies may be able to modify the sequelae of severe infection."}

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COVID-19 infection\n3.1 It is customary to divide the course of the infection into different stages: Preinfection (co-morbidities), asymptomatic, early clinical, severe clinical (acute respiratory distress syndrome–ARDS), and recovery [8,9], Fig. 2 . This natural timing should be used to establish key point-of-care sampling timepoints, avoiding patient discomfort and to focus resources. Infection can progress or be aborted at every stage, presenting a dynamic continuum, to which macrophages and monocytes contribute, together with other immune and non-immune elements; MPS contributions to COVID-19 resistance and pathogenesis are still underestimated and poorly understood.\nFig. 2 Decision points that determine the outcome of COVID-19 infection and requirements for a monocyte activation assay. A time and severity pattern has emerged for COVID-19 progression. The first days, first and second week timelines are turning points for resolution or deterioration. Epidemiologic precision for these milestones and precise parameters will be valuable for strategic sampling and patient stratification, sparing resources and patient material. With limited volumes of peripheral blood, a window on progression of the infection can be obtained by studying activation of the mononuclear phagocyte system, largely represented by monocytes in blood. The cells are biosynthetically active and relatively long lived, ideal to trace long term effects of comorbidities and infection. We highlight selected functional categories that should be addressed in monocytes and can be adapted to particular applications.\n\n3.2 Co-morbidities and the mps\nMacrophage activities contribute to many co- morbidities [8,9], including aging [28], obesity [29], diabetes [30], exposure to pollutants [31], and microbiome properties [32]. Macrophage functions alter with age, together with adaptive immune processes such as thymic involution, which deplete T lymphocyte reserves. Chronic, low grade inflammation (INFLAMMAGING) has been proposed as a predisposing factor [33]. This may result from failure of macrophages and NK cells to clear increasing accumulation of senescent cells, that enhance basal levels of inflammation and interfere with subsequent adaptive immunity upon infection [28]. Baseline inflammation may not be detrimental in itself, but can initiate an inflammatory cascade that amplifies excessive inflammation occurring in response to pathogens. Age-related metabolic correlates of macrophage dysfunction include innate lymphoid cell interactions with adipose tissue and associated macrophages, as well as inflammasome activation [34,35]. This affects thermogenesis, part of a wider metabolic syndrome involving glucose and lipid metabolism [36], elevated body mass index (BMI), type 1 and type 2 diabetes, obesity and atherosclerosis [37]. These correlate with macrophage metabolic and mitochondrial activities [38] and, possibly, ACE2 expression and hypertension, another co-morbidity [37]. ACE2, the COVID-19 entry receptor, is widely expressed on microvascular endothelium and binds the SARS-CoV2 spike glycoprotein implicated in angiotensin regulation by its competition with ACE1, and potential role as an anti-inflammatory agent [39]. Macrophages in tuberculosis and sarcoidosis express ACE1 [40], but expression of ACE2 by monocytes and tissue macrophages has not been validated [41]; evidence for productive infection of macrophages via ACE2 is incomplete [15]. Macrophages express scavenger receptors including Axl and MERTK, tyrosine kinase receptors implicated in phosphatidyl serine recognition and phagocytosis of apoptotic cells [21]; Axl is a coreceptor for ACE2+ dependent infection of other cell types by COVID-19 and other enveloped viruses via surface or endocytic routes [42], the basis for a clinical trial involving an Axl inhibitor.\nAlveolar macrophages [43] are close to Type 1 pneumocytes, involved in gas exchange, Type 2 surfactant-producing pneumocytes, and capillary endothelium, all ACE 2+ [43]. They take up and store atmospheric pollutants and poorly-degradable pro-inflammatory particles; host DNA from dying cells can induce the innate STING pathway after uptake and also activate inflammasomes in lung macrophages after exposure to ozone and cigarette smoke [31]. Other airway predisposing conditions involving macrophages [8,9], include genetic disorders such as fibrocystic disease and structural abnormalities associated with chronic inflammation and infection.\nChronic infections in which TH1-activated macrophages play a major role, tuberculosis and AIDS, enhance the risk of severe infection, with odds ratios of 1.7 and 2.3– respectively. TH2-dependent asthma may not enhance COVID-19 susceptibility, possibly correlated with low levels of ACE2 expression [44]. IL-13 also reduces ACE2 expression, suggesting that M2-macrophages may contribute to viral resistance. BCG and other immunisations may transiently promote non-specific resistance to SARS-CoV2 [45], to be confirmed in trials. Mononuclear phagocytes are implicated in selected genetic [46] or acquired systemic immunodeficiency, immunosuppression and autoimmunity, including chronic renal disease requiring organ transplantation. Tumor associated macrophages (TAM) and Myeloid derived suppressor cells (MDSC) promote malignancy and metastasis, and with chemo-and radiotherapy may enhance COVID-19 risk. Microglia contribute to neurodegeneration through interaction with neurons in Alzheimer disease, a comorbidity independent of age.\nComorbidities are likely to be multifactorial, and not all display an obvious macrophage link; for example, the ACE2 locus on the X chromosome [47] may contribute to the decreased risk of females [48], but genetic and environmental factors underlying gender, racial and individual disparities remain unclear. Therapeutics for many comorbidities impact on macrophage inflammatory and metabolic functions, including statins, sugar stabilizers, anti-hypertensives and anti-inflammatory agents; control of diabetes and obesity are important in preventing severe infection. Glucocorticoids, which have potent anti-inflammatory effects on macrophages, are contra-indicated in early infection, while protecting against severe disease; timing of administration is therefore critical [49]. The use of anti-TNF antibody in treatment of rheumatoid arthritis, protects against subsequent severe COVID-19 requiring hospitalization [50].\nIn conclusion, the present evidence for a common macrophage contribution to a range of comorbidities is correlative, rather than causal. Nor is it clear whether they increase the risk as well as the severity of infection. Macrophages are central to inflammation, immunity and metabolic diseases, but further genetic and cellular studies are needed to provide a unifying hypothesis.\n\n3.3 Asymptomatic and initial, mild infection\nThere is little direct evidence how monocytes and tissue macrophages contribute to asymptomatic infection, but their tissue distribution, receptor repertoire and secretory capacity are vital to viral resistance as well as dissemination. Acute macrophage antiviral and inflammatory responses determine the outcome of infection, together with other innate and adaptive host mechanisms. We outline evidence from clinical [20] and experimental observations from earlier [51] and current [20] coronavirus studies and consider the role of macrophages and monocytes in local and systemic infections, the antiviral and inflammatory response, resolution and complications.\nMost COVID-19 infections follow droplet inhalation and upper respiratory airway infection, which can be asymptomatic or mild, depending on mucosal immunity and IgA protection. Nasopharyngeal epithelium expresses ACE2 and is an early target for infection. Even if local tissue macrophages do not express ACE2 receptors and are not directly infected, they play a role in inflammatory cytokine responses to infected cells through surface, endosomal and cytosolic receptors and secretion of IL-1 family members [52] and antiviral interferons (IFNs). Monocytes, dendritic cells and tissue macrophages can bind virus through lectin-like receptors such as CD169 [53], for transport to regional lymph nodes. Delivery of virus droplets to the lower respiratory tract leads to infection of ACE2+ alveolar epithelium and capillary endothelium. Detection of intracellular RNA in alveolar macrophages could result from uptake of infected epithelial and endothelial cell debris rather than active infection. Single cell mRNA studies of bronchoalveolar lavage in COVID-19, have confirmed the recruitment of inflammatory monocytes as well as the presence of reactive alveolar macrophages in lung [17,18].\nSeveral common symptoms of early infection can be the indirect result of epithelial cell necrosis by viral infection mediated by ACE2 and/or other co-receptors, such as transmembrane protease serine 2, (TMPRSS2) [13]. Uptake of virus or epithelial cell debris by lung macrophages can initiate inflammasome activation by P2RX7 and release IL-1β, Type1 IFN, IL-6 and TNF [3], contributing to fever, pain, lethargy and headache. Raised levels of C-reactive protein (CRP), induced in hepatocytes by IL-6, are acute phase, plasma biomarkers of COVID-19. Other macrophage products include chemokines such as IL-8 (CXCL8) and MCP-1 (CCL2), recruiting abundant PMN and monocytes to sites of infection. Through viraemia COVID-19 reaches systemic organs such as heart, gut, brain and kidney, which contain resident and recruited macrophage populations; these contribute to local, specialised dysfunctions, such as myocarditis and cardiac arrhythmia, following interactions of macrophages and infected cardiomyocytes [54]. Intravascular coagulation [3,24] promotes dissemination of microthrombi-emboli to lungs, heart and brain, and fibrin degradation d-dimers appear in blood. This is evidence of early resolution, enhanced by the generation of antiviral IgM and IgG.\nWe have little understanding of the innate and adaptive mechanisms that fail to clear local viral infection and at what stage IFN [55,56], other pro-inflammatory [57] and haematopoietic responses become dysregulated in blood monocytes [58]. Together with compromised lung oxygenation, this can lead to systemic immune and vascular dysfunctions. A syndrome of mild infection in younger subjects gives rise to chilblain-like inflammation in toes and fingers [59]. The uncommon multisystem Kawasaki-like inflammatory syndrome of children results from atypical immune responses to COVID-19 [60,61]. This involves anti-viral antibody, systemic vasculitis affecting heart rather than lung, and can respond to corticosteroids. Apart from platelet activation, mononuclear phagocytes are known to produce tissue factor and other procoagulants [62], Factors 5 and 13; fibrinolysis by vascular endothelium and inflammatory macrophages [63] is mediated by secretion of urokinase, which cleaves plasminogen to plasmin; its activity is regulated by inhibitors in plasma, such as alpha2 macroglobulin. Anticoagulants and intranasal or inhaled Type1 IFN may be useful inhibitors of thrombosis and local viral infection, limiting progression to more severe infection.\n\n3.4 Moderate and severe infection: the hyperinflammatory syndrome\nBetween 8–12 days after COVID-19 infection, patients can progress to severe lung infection characterized by pneumonia, increased vascular permeability, edema, and hypoxia, requiring oxygen or mechanical ventilation. This is part of a systemic viral infection of ACE2+epithelia and endothelia, widespread cell death, ischaemia, hypotension and organ failure. Blood analysis at time of hospitalization, has revealed polymorphonuclear leukocytosis, altered levels of abnormal monocytes and lymphopaenia [58,64]. Myeloid cell recruitment to lung contributes to the hyperinflammatory and coagulopathy acute respiratory distress syndrome (ARDS) [20]. This is accompanied by monocyte/macrophage dysregulated production of secretory products. It is not clear which factors contribute to this complication: enhanced viral growth–perhaps triggered by early, poorly neutralizing IgM and complement or IgG, hypoxia and loss of antiviral mechanisms of macrophages–directly or secondary to lymphopaenia, massive local epithelial and endothelial necrosis, hyperactivation of newly recruited immature monocytes, or a “perfect storm” encompassing several of the above. This syndrome could be triggered by induction of ACE2 on specific populations of monocytes and macrophages, resulting in their direct infection. By this stage, spleen and draining nodes at sites of infection are severely disorganized [65]. M1-like monocytes carrying virus through CD169 or other receptors, whether infected or not, can disseminate the virus throughout the body by a Trojan horse mechanism [66]. It is not known whether lymphocytes, not infected, die by apoptosis or necrosis, from products of activated lymphocytes or macrophages such as TNF, or by phagoptosis. We summarize evidence that blood monocytes and activated tissue macrophages contribute to severe COVID-19 and consider virus-induced macrophage pathogenetic mechanisms, which can be targeted therapeutically.\nEarlier studies on SARS1/MERS revealed many of the features of ARDS and of macrophage involvement [6,51]. Initial blood and tissue analysis of COVID-19 provided morphologic evidence of monocyte abnormality and intense macrophage phagocytic activity in infected organs [65]. FACS and single cell RNA analysis of monocytes and broncho-alveolar macrophages [18] provided evidence of emergency myelopoiesis [64] and confirmed the presence of recruited and activated macrophages in alveoli [17] and lung interstitium. Plasma membrane opsonic and other receptors contribute to dysregulated inflammation, monocytic hyperactivation and impaired phagocytic clearance of apoptotic and necrotic cells and debris. Acting through NFkB, RNA, DNA and other sensing and signaling pathways, they initiate production of numerous secretory products. Particular antiviral and proinflammatory products have been targeted for anti-inflammatory treatment, including the IFNs [55,56], IL-1 family [52], IL-6 [27] and TNF [22]. In addition, mononuclear phagocytes interact with plasma cascades, and through upregulated adhesion molecules, with other myeloid and lymphoid cells, platelets, system-wide endothelia and epithelia.\nDysregulated activation of macrophages contributes to the hyperinflammatory and thrombotic pathways of severe COVID-19 [3,24,67].Virus-induced cell injury, apoptosis, necrosis and necroptosis are sensed by distinct, opposing macrophage receptor-dependent effector responses. These include activating and inhibitory pathways of IL-1 production, processing and secretion [52,57], triggered by tissue injury, inflammasome and caspase activation. A highly impaired type1 IFN response, characterized by no IFNβ and low IFNα production and activity, has been associated with persistent viraemia and an exacerbated inflammatory response, partially driven by NFkB, TNF and IL-6 [56]. Endogenous oxidized phospholipids reprogramme macrophage metabolism and boost hyperinflammation [68]. By capturing inflammatory lipids released from dying cells, CD14 induces inflammasome-dependent phagocyte hyperactivation [69]. Macrophage fuel production and utilization [36] are sensitive to hypoxia, HIF-1 responses [70] and iron availability, influencing M1 polarization and effector functions. Activated macrophages trigger coagulation and complement cascades, as well as angiotensin and bradykinin pathways that dysregulate vascular tone and permeability, exacerbating inflammation and edema.\nImmunological processes that may contribute to the outcome of macrophage- viral induced pathology include antibody enhancement of infection (ADE) and inflammation (ADI), and neutrophil NETosis. Anti-spike antiserum can induce hyperinflammation via macrophage FcR, depending on IgG glycosylation and Syk involvement [71]. Cross-reacting antibodies from previous benign coronavirus infections also contribute to enhanced pathology [72]. Dendritic cell dysfunction, ascribed to down regulated HLA-DR expression [67,72] and defective antigen presentation to T and B lymphocytes, may result from lack of costimulatory signals, aborting lymphocyte proliferation and activation and mediating widespread clonal death. Haemophagocytosis, a feature of the macrophage activation syndrome (MAS), is also observed in other viral infections.\n\n3.5 Recovery\nMacrophages are central to the cellular processes which contribute to recovery from COVID-19 infection; they remove debris and necrotic tissue through phagocytosis and secretion of elastase and collagenase, and produce IGF1 and TGF-β to promote tissue recovery. M2-like macrophages are the source of potent lipid metabolites which resolve inflammation; these include resolvins, protectins and maresins, short lived autacoids which regulate the magnitude and duration of acute inflammation [25,73]. Acting through macrophage GPCRs for these metabolites, they enhance efferocytosis of dying neutrophils, and counter inflammation without immunosuppression.\nRecovery can be prolonged after severe infection, involving fever, lethargy, scarring and loss of organ function. Italiani and colleagues profiled the course of resolving versus persistent inflammation with special reference to IL-1 family molecules [57]. An independent single cell mRNA analysis of peripheral blood mononuclear cells during early recovery of COVID-19 infection [23], revealed an increased ratio and level of classical CD14++IL-1β+ monocytes. Further studies are needed to compare monocytes and tissue macrophages after mild or severe infection and to establish whether repolarisation of macrophages from M1 to an M2 phenotype can promote resolution and recovery after COVID-19. After helminth infection, M2 macrophages express resistin, which protects against LPS-induced toxic shock [74]. New or repurposed therapies may be able to modify the sequelae of severe infection."}

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COVID-19 infection\n3.1 It is customary to divide the course of the infection into different stages: Preinfection (co-morbidities), asymptomatic, early clinical, severe clinical (acute respiratory distress syndrome–ARDS), and recovery [8,9], Fig. 2 . This natural timing should be used to establish key point-of-care sampling timepoints, avoiding patient discomfort and to focus resources. Infection can progress or be aborted at every stage, presenting a dynamic continuum, to which macrophages and monocytes contribute, together with other immune and non-immune elements; MPS contributions to COVID-19 resistance and pathogenesis are still underestimated and poorly understood.\nFig. 2 Decision points that determine the outcome of COVID-19 infection and requirements for a monocyte activation assay. A time and severity pattern has emerged for COVID-19 progression. The first days, first and second week timelines are turning points for resolution or deterioration. Epidemiologic precision for these milestones and precise parameters will be valuable for strategic sampling and patient stratification, sparing resources and patient material. With limited volumes of peripheral blood, a window on progression of the infection can be obtained by studying activation of the mononuclear phagocyte system, largely represented by monocytes in blood. The cells are biosynthetically active and relatively long lived, ideal to trace long term effects of comorbidities and infection. We highlight selected functional categories that should be addressed in monocytes and can be adapted to particular applications.\n\n3.2 Co-morbidities and the mps\nMacrophage activities contribute to many co- morbidities [8,9], including aging [28], obesity [29], diabetes [30], exposure to pollutants [31], and microbiome properties [32]. Macrophage functions alter with age, together with adaptive immune processes such as thymic involution, which deplete T lymphocyte reserves. Chronic, low grade inflammation (INFLAMMAGING) has been proposed as a predisposing factor [33]. This may result from failure of macrophages and NK cells to clear increasing accumulation of senescent cells, that enhance basal levels of inflammation and interfere with subsequent adaptive immunity upon infection [28]. Baseline inflammation may not be detrimental in itself, but can initiate an inflammatory cascade that amplifies excessive inflammation occurring in response to pathogens. Age-related metabolic correlates of macrophage dysfunction include innate lymphoid cell interactions with adipose tissue and associated macrophages, as well as inflammasome activation [34,35]. This affects thermogenesis, part of a wider metabolic syndrome involving glucose and lipid metabolism [36], elevated body mass index (BMI), type 1 and type 2 diabetes, obesity and atherosclerosis [37]. These correlate with macrophage metabolic and mitochondrial activities [38] and, possibly, ACE2 expression and hypertension, another co-morbidity [37]. ACE2, the COVID-19 entry receptor, is widely expressed on microvascular endothelium and binds the SARS-CoV2 spike glycoprotein implicated in angiotensin regulation by its competition with ACE1, and potential role as an anti-inflammatory agent [39]. Macrophages in tuberculosis and sarcoidosis express ACE1 [40], but expression of ACE2 by monocytes and tissue macrophages has not been validated [41]; evidence for productive infection of macrophages via ACE2 is incomplete [15]. Macrophages express scavenger receptors including Axl and MERTK, tyrosine kinase receptors implicated in phosphatidyl serine recognition and phagocytosis of apoptotic cells [21]; Axl is a coreceptor for ACE2+ dependent infection of other cell types by COVID-19 and other enveloped viruses via surface or endocytic routes [42], the basis for a clinical trial involving an Axl inhibitor.\nAlveolar macrophages [43] are close to Type 1 pneumocytes, involved in gas exchange, Type 2 surfactant-producing pneumocytes, and capillary endothelium, all ACE 2+ [43]. They take up and store atmospheric pollutants and poorly-degradable pro-inflammatory particles; host DNA from dying cells can induce the innate STING pathway after uptake and also activate inflammasomes in lung macrophages after exposure to ozone and cigarette smoke [31]. Other airway predisposing conditions involving macrophages [8,9], include genetic disorders such as fibrocystic disease and structural abnormalities associated with chronic inflammation and infection.\nChronic infections in which TH1-activated macrophages play a major role, tuberculosis and AIDS, enhance the risk of severe infection, with odds ratios of 1.7 and 2.3– respectively. TH2-dependent asthma may not enhance COVID-19 susceptibility, possibly correlated with low levels of ACE2 expression [44]. IL-13 also reduces ACE2 expression, suggesting that M2-macrophages may contribute to viral resistance. BCG and other immunisations may transiently promote non-specific resistance to SARS-CoV2 [45], to be confirmed in trials. Mononuclear phagocytes are implicated in selected genetic [46] or acquired systemic immunodeficiency, immunosuppression and autoimmunity, including chronic renal disease requiring organ transplantation. Tumor associated macrophages (TAM) and Myeloid derived suppressor cells (MDSC) promote malignancy and metastasis, and with chemo-and radiotherapy may enhance COVID-19 risk. Microglia contribute to neurodegeneration through interaction with neurons in Alzheimer disease, a comorbidity independent of age.\nComorbidities are likely to be multifactorial, and not all display an obvious macrophage link; for example, the ACE2 locus on the X chromosome [47] may contribute to the decreased risk of females [48], but genetic and environmental factors underlying gender, racial and individual disparities remain unclear. Therapeutics for many comorbidities impact on macrophage inflammatory and metabolic functions, including statins, sugar stabilizers, anti-hypertensives and anti-inflammatory agents; control of diabetes and obesity are important in preventing severe infection. Glucocorticoids, which have potent anti-inflammatory effects on macrophages, are contra-indicated in early infection, while protecting against severe disease; timing of administration is therefore critical [49]. The use of anti-TNF antibody in treatment of rheumatoid arthritis, protects against subsequent severe COVID-19 requiring hospitalization [50].\nIn conclusion, the present evidence for a common macrophage contribution to a range of comorbidities is correlative, rather than causal. Nor is it clear whether they increase the risk as well as the severity of infection. Macrophages are central to inflammation, immunity and metabolic diseases, but further genetic and cellular studies are needed to provide a unifying hypothesis.\n\n3.3 Asymptomatic and initial, mild infection\nThere is little direct evidence how monocytes and tissue macrophages contribute to asymptomatic infection, but their tissue distribution, receptor repertoire and secretory capacity are vital to viral resistance as well as dissemination. Acute macrophage antiviral and inflammatory responses determine the outcome of infection, together with other innate and adaptive host mechanisms. We outline evidence from clinical [20] and experimental observations from earlier [51] and current [20] coronavirus studies and consider the role of macrophages and monocytes in local and systemic infections, the antiviral and inflammatory response, resolution and complications.\nMost COVID-19 infections follow droplet inhalation and upper respiratory airway infection, which can be asymptomatic or mild, depending on mucosal immunity and IgA protection. Nasopharyngeal epithelium expresses ACE2 and is an early target for infection. Even if local tissue macrophages do not express ACE2 receptors and are not directly infected, they play a role in inflammatory cytokine responses to infected cells through surface, endosomal and cytosolic receptors and secretion of IL-1 family members [52] and antiviral interferons (IFNs). Monocytes, dendritic cells and tissue macrophages can bind virus through lectin-like receptors such as CD169 [53], for transport to regional lymph nodes. Delivery of virus droplets to the lower respiratory tract leads to infection of ACE2+ alveolar epithelium and capillary endothelium. Detection of intracellular RNA in alveolar macrophages could result from uptake of infected epithelial and endothelial cell debris rather than active infection. Single cell mRNA studies of bronchoalveolar lavage in COVID-19, have confirmed the recruitment of inflammatory monocytes as well as the presence of reactive alveolar macrophages in lung [17,18].\nSeveral common symptoms of early infection can be the indirect result of epithelial cell necrosis by viral infection mediated by ACE2 and/or other co-receptors, such as transmembrane protease serine 2, (TMPRSS2) [13]. Uptake of virus or epithelial cell debris by lung macrophages can initiate inflammasome activation by P2RX7 and release IL-1β, Type1 IFN, IL-6 and TNF [3], contributing to fever, pain, lethargy and headache. Raised levels of C-reactive protein (CRP), induced in hepatocytes by IL-6, are acute phase, plasma biomarkers of COVID-19. Other macrophage products include chemokines such as IL-8 (CXCL8) and MCP-1 (CCL2), recruiting abundant PMN and monocytes to sites of infection. Through viraemia COVID-19 reaches systemic organs such as heart, gut, brain and kidney, which contain resident and recruited macrophage populations; these contribute to local, specialised dysfunctions, such as myocarditis and cardiac arrhythmia, following interactions of macrophages and infected cardiomyocytes [54]. Intravascular coagulation [3,24] promotes dissemination of microthrombi-emboli to lungs, heart and brain, and fibrin degradation d-dimers appear in blood. This is evidence of early resolution, enhanced by the generation of antiviral IgM and IgG.\nWe have little understanding of the innate and adaptive mechanisms that fail to clear local viral infection and at what stage IFN [55,56], other pro-inflammatory [57] and haematopoietic responses become dysregulated in blood monocytes [58]. Together with compromised lung oxygenation, this can lead to systemic immune and vascular dysfunctions. A syndrome of mild infection in younger subjects gives rise to chilblain-like inflammation in toes and fingers [59]. The uncommon multisystem Kawasaki-like inflammatory syndrome of children results from atypical immune responses to COVID-19 [60,61]. This involves anti-viral antibody, systemic vasculitis affecting heart rather than lung, and can respond to corticosteroids. Apart from platelet activation, mononuclear phagocytes are known to produce tissue factor and other procoagulants [62], Factors 5 and 13; fibrinolysis by vascular endothelium and inflammatory macrophages [63] is mediated by secretion of urokinase, which cleaves plasminogen to plasmin; its activity is regulated by inhibitors in plasma, such as alpha2 macroglobulin. Anticoagulants and intranasal or inhaled Type1 IFN may be useful inhibitors of thrombosis and local viral infection, limiting progression to more severe infection.\n\n3.4 Moderate and severe infection: the hyperinflammatory syndrome\nBetween 8–12 days after COVID-19 infection, patients can progress to severe lung infection characterized by pneumonia, increased vascular permeability, edema, and hypoxia, requiring oxygen or mechanical ventilation. This is part of a systemic viral infection of ACE2+epithelia and endothelia, widespread cell death, ischaemia, hypotension and organ failure. Blood analysis at time of hospitalization, has revealed polymorphonuclear leukocytosis, altered levels of abnormal monocytes and lymphopaenia [58,64]. Myeloid cell recruitment to lung contributes to the hyperinflammatory and coagulopathy acute respiratory distress syndrome (ARDS) [20]. This is accompanied by monocyte/macrophage dysregulated production of secretory products. It is not clear which factors contribute to this complication: enhanced viral growth–perhaps triggered by early, poorly neutralizing IgM and complement or IgG, hypoxia and loss of antiviral mechanisms of macrophages–directly or secondary to lymphopaenia, massive local epithelial and endothelial necrosis, hyperactivation of newly recruited immature monocytes, or a “perfect storm” encompassing several of the above. This syndrome could be triggered by induction of ACE2 on specific populations of monocytes and macrophages, resulting in their direct infection. By this stage, spleen and draining nodes at sites of infection are severely disorganized [65]. M1-like monocytes carrying virus through CD169 or other receptors, whether infected or not, can disseminate the virus throughout the body by a Trojan horse mechanism [66]. It is not known whether lymphocytes, not infected, die by apoptosis or necrosis, from products of activated lymphocytes or macrophages such as TNF, or by phagoptosis. We summarize evidence that blood monocytes and activated tissue macrophages contribute to severe COVID-19 and consider virus-induced macrophage pathogenetic mechanisms, which can be targeted therapeutically.\nEarlier studies on SARS1/MERS revealed many of the features of ARDS and of macrophage involvement [6,51]. Initial blood and tissue analysis of COVID-19 provided morphologic evidence of monocyte abnormality and intense macrophage phagocytic activity in infected organs [65]. FACS and single cell RNA analysis of monocytes and broncho-alveolar macrophages [18] provided evidence of emergency myelopoiesis [64] and confirmed the presence of recruited and activated macrophages in alveoli [17] and lung interstitium. Plasma membrane opsonic and other receptors contribute to dysregulated inflammation, monocytic hyperactivation and impaired phagocytic clearance of apoptotic and necrotic cells and debris. Acting through NFkB, RNA, DNA and other sensing and signaling pathways, they initiate production of numerous secretory products. Particular antiviral and proinflammatory products have been targeted for anti-inflammatory treatment, including the IFNs [55,56], IL-1 family [52], IL-6 [27] and TNF [22]. In addition, mononuclear phagocytes interact with plasma cascades, and through upregulated adhesion molecules, with other myeloid and lymphoid cells, platelets, system-wide endothelia and epithelia.\nDysregulated activation of macrophages contributes to the hyperinflammatory and thrombotic pathways of severe COVID-19 [3,24,67].Virus-induced cell injury, apoptosis, necrosis and necroptosis are sensed by distinct, opposing macrophage receptor-dependent effector responses. These include activating and inhibitory pathways of IL-1 production, processing and secretion [52,57], triggered by tissue injury, inflammasome and caspase activation. A highly impaired type1 IFN response, characterized by no IFNβ and low IFNα production and activity, has been associated with persistent viraemia and an exacerbated inflammatory response, partially driven by NFkB, TNF and IL-6 [56]. Endogenous oxidized phospholipids reprogramme macrophage metabolism and boost hyperinflammation [68]. By capturing inflammatory lipids released from dying cells, CD14 induces inflammasome-dependent phagocyte hyperactivation [69]. Macrophage fuel production and utilization [36] are sensitive to hypoxia, HIF-1 responses [70] and iron availability, influencing M1 polarization and effector functions. Activated macrophages trigger coagulation and complement cascades, as well as angiotensin and bradykinin pathways that dysregulate vascular tone and permeability, exacerbating inflammation and edema.\nImmunological processes that may contribute to the outcome of macrophage- viral induced pathology include antibody enhancement of infection (ADE) and inflammation (ADI), and neutrophil NETosis. Anti-spike antiserum can induce hyperinflammation via macrophage FcR, depending on IgG glycosylation and Syk involvement [71]. Cross-reacting antibodies from previous benign coronavirus infections also contribute to enhanced pathology [72]. Dendritic cell dysfunction, ascribed to down regulated HLA-DR expression [67,72] and defective antigen presentation to T and B lymphocytes, may result from lack of costimulatory signals, aborting lymphocyte proliferation and activation and mediating widespread clonal death. Haemophagocytosis, a feature of the macrophage activation syndrome (MAS), is also observed in other viral infections.\n\n3.5 Recovery\nMacrophages are central to the cellular processes which contribute to recovery from COVID-19 infection; they remove debris and necrotic tissue through phagocytosis and secretion of elastase and collagenase, and produce IGF1 and TGF-β to promote tissue recovery. M2-like macrophages are the source of potent lipid metabolites which resolve inflammation; these include resolvins, protectins and maresins, short lived autacoids which regulate the magnitude and duration of acute inflammation [25,73]. Acting through macrophage GPCRs for these metabolites, they enhance efferocytosis of dying neutrophils, and counter inflammation without immunosuppression.\nRecovery can be prolonged after severe infection, involving fever, lethargy, scarring and loss of organ function. Italiani and colleagues profiled the course of resolving versus persistent inflammation with special reference to IL-1 family molecules [57]. An independent single cell mRNA analysis of peripheral blood mononuclear cells during early recovery of COVID-19 infection [23], revealed an increased ratio and level of classical CD14++IL-1β+ monocytes. Further studies are needed to compare monocytes and tissue macrophages after mild or severe infection and to establish whether repolarisation of macrophages from M1 to an M2 phenotype can promote resolution and recovery after COVID-19. After helminth infection, M2 macrophages express resistin, which protects against LPS-induced toxic shock [74]. New or repurposed therapies may be able to modify the sequelae of severe infection."}

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COVID-19 infection\n3.1 It is customary to divide the course of the infection into different stages: Preinfection (co-morbidities), asymptomatic, early clinical, severe clinical (acute respiratory distress syndrome–ARDS), and recovery [8,9], Fig. 2 . This natural timing should be used to establish key point-of-care sampling timepoints, avoiding patient discomfort and to focus resources. Infection can progress or be aborted at every stage, presenting a dynamic continuum, to which macrophages and monocytes contribute, together with other immune and non-immune elements; MPS contributions to COVID-19 resistance and pathogenesis are still underestimated and poorly understood.\nFig. 2 Decision points that determine the outcome of COVID-19 infection and requirements for a monocyte activation assay. A time and severity pattern has emerged for COVID-19 progression. The first days, first and second week timelines are turning points for resolution or deterioration. Epidemiologic precision for these milestones and precise parameters will be valuable for strategic sampling and patient stratification, sparing resources and patient material. With limited volumes of peripheral blood, a window on progression of the infection can be obtained by studying activation of the mononuclear phagocyte system, largely represented by monocytes in blood. The cells are biosynthetically active and relatively long lived, ideal to trace long term effects of comorbidities and infection. We highlight selected functional categories that should be addressed in monocytes and can be adapted to particular applications.\n\n3.2 Co-morbidities and the mps\nMacrophage activities contribute to many co- morbidities [8,9], including aging [28], obesity [29], diabetes [30], exposure to pollutants [31], and microbiome properties [32]. Macrophage functions alter with age, together with adaptive immune processes such as thymic involution, which deplete T lymphocyte reserves. Chronic, low grade inflammation (INFLAMMAGING) has been proposed as a predisposing factor [33]. This may result from failure of macrophages and NK cells to clear increasing accumulation of senescent cells, that enhance basal levels of inflammation and interfere with subsequent adaptive immunity upon infection [28]. Baseline inflammation may not be detrimental in itself, but can initiate an inflammatory cascade that amplifies excessive inflammation occurring in response to pathogens. Age-related metabolic correlates of macrophage dysfunction include innate lymphoid cell interactions with adipose tissue and associated macrophages, as well as inflammasome activation [34,35]. This affects thermogenesis, part of a wider metabolic syndrome involving glucose and lipid metabolism [36], elevated body mass index (BMI), type 1 and type 2 diabetes, obesity and atherosclerosis [37]. These correlate with macrophage metabolic and mitochondrial activities [38] and, possibly, ACE2 expression and hypertension, another co-morbidity [37]. ACE2, the COVID-19 entry receptor, is widely expressed on microvascular endothelium and binds the SARS-CoV2 spike glycoprotein implicated in angiotensin regulation by its competition with ACE1, and potential role as an anti-inflammatory agent [39]. Macrophages in tuberculosis and sarcoidosis express ACE1 [40], but expression of ACE2 by monocytes and tissue macrophages has not been validated [41]; evidence for productive infection of macrophages via ACE2 is incomplete [15]. Macrophages express scavenger receptors including Axl and MERTK, tyrosine kinase receptors implicated in phosphatidyl serine recognition and phagocytosis of apoptotic cells [21]; Axl is a coreceptor for ACE2+ dependent infection of other cell types by COVID-19 and other enveloped viruses via surface or endocytic routes [42], the basis for a clinical trial involving an Axl inhibitor.\nAlveolar macrophages [43] are close to Type 1 pneumocytes, involved in gas exchange, Type 2 surfactant-producing pneumocytes, and capillary endothelium, all ACE 2+ [43]. They take up and store atmospheric pollutants and poorly-degradable pro-inflammatory particles; host DNA from dying cells can induce the innate STING pathway after uptake and also activate inflammasomes in lung macrophages after exposure to ozone and cigarette smoke [31]. Other airway predisposing conditions involving macrophages [8,9], include genetic disorders such as fibrocystic disease and structural abnormalities associated with chronic inflammation and infection.\nChronic infections in which TH1-activated macrophages play a major role, tuberculosis and AIDS, enhance the risk of severe infection, with odds ratios of 1.7 and 2.3– respectively. TH2-dependent asthma may not enhance COVID-19 susceptibility, possibly correlated with low levels of ACE2 expression [44]. IL-13 also reduces ACE2 expression, suggesting that M2-macrophages may contribute to viral resistance. BCG and other immunisations may transiently promote non-specific resistance to SARS-CoV2 [45], to be confirmed in trials. Mononuclear phagocytes are implicated in selected genetic [46] or acquired systemic immunodeficiency, immunosuppression and autoimmunity, including chronic renal disease requiring organ transplantation. Tumor associated macrophages (TAM) and Myeloid derived suppressor cells (MDSC) promote malignancy and metastasis, and with chemo-and radiotherapy may enhance COVID-19 risk. Microglia contribute to neurodegeneration through interaction with neurons in Alzheimer disease, a comorbidity independent of age.\nComorbidities are likely to be multifactorial, and not all display an obvious macrophage link; for example, the ACE2 locus on the X chromosome [47] may contribute to the decreased risk of females [48], but genetic and environmental factors underlying gender, racial and individual disparities remain unclear. Therapeutics for many comorbidities impact on macrophage inflammatory and metabolic functions, including statins, sugar stabilizers, anti-hypertensives and anti-inflammatory agents; control of diabetes and obesity are important in preventing severe infection. Glucocorticoids, which have potent anti-inflammatory effects on macrophages, are contra-indicated in early infection, while protecting against severe disease; timing of administration is therefore critical [49]. The use of anti-TNF antibody in treatment of rheumatoid arthritis, protects against subsequent severe COVID-19 requiring hospitalization [50].\nIn conclusion, the present evidence for a common macrophage contribution to a range of comorbidities is correlative, rather than causal. Nor is it clear whether they increase the risk as well as the severity of infection. Macrophages are central to inflammation, immunity and metabolic diseases, but further genetic and cellular studies are needed to provide a unifying hypothesis.\n\n3.3 Asymptomatic and initial, mild infection\nThere is little direct evidence how monocytes and tissue macrophages contribute to asymptomatic infection, but their tissue distribution, receptor repertoire and secretory capacity are vital to viral resistance as well as dissemination. Acute macrophage antiviral and inflammatory responses determine the outcome of infection, together with other innate and adaptive host mechanisms. We outline evidence from clinical [20] and experimental observations from earlier [51] and current [20] coronavirus studies and consider the role of macrophages and monocytes in local and systemic infections, the antiviral and inflammatory response, resolution and complications.\nMost COVID-19 infections follow droplet inhalation and upper respiratory airway infection, which can be asymptomatic or mild, depending on mucosal immunity and IgA protection. Nasopharyngeal epithelium expresses ACE2 and is an early target for infection. Even if local tissue macrophages do not express ACE2 receptors and are not directly infected, they play a role in inflammatory cytokine responses to infected cells through surface, endosomal and cytosolic receptors and secretion of IL-1 family members [52] and antiviral interferons (IFNs). Monocytes, dendritic cells and tissue macrophages can bind virus through lectin-like receptors such as CD169 [53], for transport to regional lymph nodes. Delivery of virus droplets to the lower respiratory tract leads to infection of ACE2+ alveolar epithelium and capillary endothelium. Detection of intracellular RNA in alveolar macrophages could result from uptake of infected epithelial and endothelial cell debris rather than active infection. Single cell mRNA studies of bronchoalveolar lavage in COVID-19, have confirmed the recruitment of inflammatory monocytes as well as the presence of reactive alveolar macrophages in lung [17,18].\nSeveral common symptoms of early infection can be the indirect result of epithelial cell necrosis by viral infection mediated by ACE2 and/or other co-receptors, such as transmembrane protease serine 2, (TMPRSS2) [13]. Uptake of virus or epithelial cell debris by lung macrophages can initiate inflammasome activation by P2RX7 and release IL-1β, Type1 IFN, IL-6 and TNF [3], contributing to fever, pain, lethargy and headache. Raised levels of C-reactive protein (CRP), induced in hepatocytes by IL-6, are acute phase, plasma biomarkers of COVID-19. Other macrophage products include chemokines such as IL-8 (CXCL8) and MCP-1 (CCL2), recruiting abundant PMN and monocytes to sites of infection. Through viraemia COVID-19 reaches systemic organs such as heart, gut, brain and kidney, which contain resident and recruited macrophage populations; these contribute to local, specialised dysfunctions, such as myocarditis and cardiac arrhythmia, following interactions of macrophages and infected cardiomyocytes [54]. Intravascular coagulation [3,24] promotes dissemination of microthrombi-emboli to lungs, heart and brain, and fibrin degradation d-dimers appear in blood. This is evidence of early resolution, enhanced by the generation of antiviral IgM and IgG.\nWe have little understanding of the innate and adaptive mechanisms that fail to clear local viral infection and at what stage IFN [55,56], other pro-inflammatory [57] and haematopoietic responses become dysregulated in blood monocytes [58]. Together with compromised lung oxygenation, this can lead to systemic immune and vascular dysfunctions. A syndrome of mild infection in younger subjects gives rise to chilblain-like inflammation in toes and fingers [59]. The uncommon multisystem Kawasaki-like inflammatory syndrome of children results from atypical immune responses to COVID-19 [60,61]. This involves anti-viral antibody, systemic vasculitis affecting heart rather than lung, and can respond to corticosteroids. Apart from platelet activation, mononuclear phagocytes are known to produce tissue factor and other procoagulants [62], Factors 5 and 13; fibrinolysis by vascular endothelium and inflammatory macrophages [63] is mediated by secretion of urokinase, which cleaves plasminogen to plasmin; its activity is regulated by inhibitors in plasma, such as alpha2 macroglobulin. Anticoagulants and intranasal or inhaled Type1 IFN may be useful inhibitors of thrombosis and local viral infection, limiting progression to more severe infection.\n\n3.4 Moderate and severe infection: the hyperinflammatory syndrome\nBetween 8–12 days after COVID-19 infection, patients can progress to severe lung infection characterized by pneumonia, increased vascular permeability, edema, and hypoxia, requiring oxygen or mechanical ventilation. This is part of a systemic viral infection of ACE2+epithelia and endothelia, widespread cell death, ischaemia, hypotension and organ failure. Blood analysis at time of hospitalization, has revealed polymorphonuclear leukocytosis, altered levels of abnormal monocytes and lymphopaenia [58,64]. Myeloid cell recruitment to lung contributes to the hyperinflammatory and coagulopathy acute respiratory distress syndrome (ARDS) [20]. This is accompanied by monocyte/macrophage dysregulated production of secretory products. It is not clear which factors contribute to this complication: enhanced viral growth–perhaps triggered by early, poorly neutralizing IgM and complement or IgG, hypoxia and loss of antiviral mechanisms of macrophages–directly or secondary to lymphopaenia, massive local epithelial and endothelial necrosis, hyperactivation of newly recruited immature monocytes, or a “perfect storm” encompassing several of the above. This syndrome could be triggered by induction of ACE2 on specific populations of monocytes and macrophages, resulting in their direct infection. By this stage, spleen and draining nodes at sites of infection are severely disorganized [65]. M1-like monocytes carrying virus through CD169 or other receptors, whether infected or not, can disseminate the virus throughout the body by a Trojan horse mechanism [66]. It is not known whether lymphocytes, not infected, die by apoptosis or necrosis, from products of activated lymphocytes or macrophages such as TNF, or by phagoptosis. We summarize evidence that blood monocytes and activated tissue macrophages contribute to severe COVID-19 and consider virus-induced macrophage pathogenetic mechanisms, which can be targeted therapeutically.\nEarlier studies on SARS1/MERS revealed many of the features of ARDS and of macrophage involvement [6,51]. Initial blood and tissue analysis of COVID-19 provided morphologic evidence of monocyte abnormality and intense macrophage phagocytic activity in infected organs [65]. FACS and single cell RNA analysis of monocytes and broncho-alveolar macrophages [18] provided evidence of emergency myelopoiesis [64] and confirmed the presence of recruited and activated macrophages in alveoli [17] and lung interstitium. Plasma membrane opsonic and other receptors contribute to dysregulated inflammation, monocytic hyperactivation and impaired phagocytic clearance of apoptotic and necrotic cells and debris. Acting through NFkB, RNA, DNA and other sensing and signaling pathways, they initiate production of numerous secretory products. Particular antiviral and proinflammatory products have been targeted for anti-inflammatory treatment, including the IFNs [55,56], IL-1 family [52], IL-6 [27] and TNF [22]. In addition, mononuclear phagocytes interact with plasma cascades, and through upregulated adhesion molecules, with other myeloid and lymphoid cells, platelets, system-wide endothelia and epithelia.\nDysregulated activation of macrophages contributes to the hyperinflammatory and thrombotic pathways of severe COVID-19 [3,24,67].Virus-induced cell injury, apoptosis, necrosis and necroptosis are sensed by distinct, opposing macrophage receptor-dependent effector responses. These include activating and inhibitory pathways of IL-1 production, processing and secretion [52,57], triggered by tissue injury, inflammasome and caspase activation. A highly impaired type1 IFN response, characterized by no IFNβ and low IFNα production and activity, has been associated with persistent viraemia and an exacerbated inflammatory response, partially driven by NFkB, TNF and IL-6 [56]. Endogenous oxidized phospholipids reprogramme macrophage metabolism and boost hyperinflammation [68]. By capturing inflammatory lipids released from dying cells, CD14 induces inflammasome-dependent phagocyte hyperactivation [69]. Macrophage fuel production and utilization [36] are sensitive to hypoxia, HIF-1 responses [70] and iron availability, influencing M1 polarization and effector functions. Activated macrophages trigger coagulation and complement cascades, as well as angiotensin and bradykinin pathways that dysregulate vascular tone and permeability, exacerbating inflammation and edema.\nImmunological processes that may contribute to the outcome of macrophage- viral induced pathology include antibody enhancement of infection (ADE) and inflammation (ADI), and neutrophil NETosis. Anti-spike antiserum can induce hyperinflammation via macrophage FcR, depending on IgG glycosylation and Syk involvement [71]. Cross-reacting antibodies from previous benign coronavirus infections also contribute to enhanced pathology [72]. Dendritic cell dysfunction, ascribed to down regulated HLA-DR expression [67,72] and defective antigen presentation to T and B lymphocytes, may result from lack of costimulatory signals, aborting lymphocyte proliferation and activation and mediating widespread clonal death. Haemophagocytosis, a feature of the macrophage activation syndrome (MAS), is also observed in other viral infections.\n\n3.5 Recovery\nMacrophages are central to the cellular processes which contribute to recovery from COVID-19 infection; they remove debris and necrotic tissue through phagocytosis and secretion of elastase and collagenase, and produce IGF1 and TGF-β to promote tissue recovery. M2-like macrophages are the source of potent lipid metabolites which resolve inflammation; these include resolvins, protectins and maresins, short lived autacoids which regulate the magnitude and duration of acute inflammation [25,73]. Acting through macrophage GPCRs for these metabolites, they enhance efferocytosis of dying neutrophils, and counter inflammation without immunosuppression.\nRecovery can be prolonged after severe infection, involving fever, lethargy, scarring and loss of organ function. Italiani and colleagues profiled the course of resolving versus persistent inflammation with special reference to IL-1 family molecules [57]. An independent single cell mRNA analysis of peripheral blood mononuclear cells during early recovery of COVID-19 infection [23], revealed an increased ratio and level of classical CD14++IL-1β+ monocytes. Further studies are needed to compare monocytes and tissue macrophages after mild or severe infection and to establish whether repolarisation of macrophages from M1 to an M2 phenotype can promote resolution and recovery after COVID-19. After helminth infection, M2 macrophages express resistin, which protects against LPS-induced toxic shock [74]. New or repurposed therapies may be able to modify the sequelae of severe infection."}

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COVID-19 infection\n3.1 It is customary to divide the course of the infection into different stages: Preinfection (co-morbidities), asymptomatic, early clinical, severe clinical (acute respiratory distress syndrome–ARDS), and recovery [8,9], Fig. 2 . This natural timing should be used to establish key point-of-care sampling timepoints, avoiding patient discomfort and to focus resources. Infection can progress or be aborted at every stage, presenting a dynamic continuum, to which macrophages and monocytes contribute, together with other immune and non-immune elements; MPS contributions to COVID-19 resistance and pathogenesis are still underestimated and poorly understood.\nFig. 2 Decision points that determine the outcome of COVID-19 infection and requirements for a monocyte activation assay. A time and severity pattern has emerged for COVID-19 progression. The first days, first and second week timelines are turning points for resolution or deterioration. Epidemiologic precision for these milestones and precise parameters will be valuable for strategic sampling and patient stratification, sparing resources and patient material. With limited volumes of peripheral blood, a window on progression of the infection can be obtained by studying activation of the mononuclear phagocyte system, largely represented by monocytes in blood. The cells are biosynthetically active and relatively long lived, ideal to trace long term effects of comorbidities and infection. We highlight selected functional categories that should be addressed in monocytes and can be adapted to particular applications.\n\n3.2 Co-morbidities and the mps\nMacrophage activities contribute to many co- morbidities [8,9], including aging [28], obesity [29], diabetes [30], exposure to pollutants [31], and microbiome properties [32]. Macrophage functions alter with age, together with adaptive immune processes such as thymic involution, which deplete T lymphocyte reserves. Chronic, low grade inflammation (INFLAMMAGING) has been proposed as a predisposing factor [33]. This may result from failure of macrophages and NK cells to clear increasing accumulation of senescent cells, that enhance basal levels of inflammation and interfere with subsequent adaptive immunity upon infection [28]. Baseline inflammation may not be detrimental in itself, but can initiate an inflammatory cascade that amplifies excessive inflammation occurring in response to pathogens. Age-related metabolic correlates of macrophage dysfunction include innate lymphoid cell interactions with adipose tissue and associated macrophages, as well as inflammasome activation [34,35]. This affects thermogenesis, part of a wider metabolic syndrome involving glucose and lipid metabolism [36], elevated body mass index (BMI), type 1 and type 2 diabetes, obesity and atherosclerosis [37]. These correlate with macrophage metabolic and mitochondrial activities [38] and, possibly, ACE2 expression and hypertension, another co-morbidity [37]. ACE2, the COVID-19 entry receptor, is widely expressed on microvascular endothelium and binds the SARS-CoV2 spike glycoprotein implicated in angiotensin regulation by its competition with ACE1, and potential role as an anti-inflammatory agent [39]. Macrophages in tuberculosis and sarcoidosis express ACE1 [40], but expression of ACE2 by monocytes and tissue macrophages has not been validated [41]; evidence for productive infection of macrophages via ACE2 is incomplete [15]. Macrophages express scavenger receptors including Axl and MERTK, tyrosine kinase receptors implicated in phosphatidyl serine recognition and phagocytosis of apoptotic cells [21]; Axl is a coreceptor for ACE2+ dependent infection of other cell types by COVID-19 and other enveloped viruses via surface or endocytic routes [42], the basis for a clinical trial involving an Axl inhibitor.\nAlveolar macrophages [43] are close to Type 1 pneumocytes, involved in gas exchange, Type 2 surfactant-producing pneumocytes, and capillary endothelium, all ACE 2+ [43]. They take up and store atmospheric pollutants and poorly-degradable pro-inflammatory particles; host DNA from dying cells can induce the innate STING pathway after uptake and also activate inflammasomes in lung macrophages after exposure to ozone and cigarette smoke [31]. Other airway predisposing conditions involving macrophages [8,9], include genetic disorders such as fibrocystic disease and structural abnormalities associated with chronic inflammation and infection.\nChronic infections in which TH1-activated macrophages play a major role, tuberculosis and AIDS, enhance the risk of severe infection, with odds ratios of 1.7 and 2.3– respectively. TH2-dependent asthma may not enhance COVID-19 susceptibility, possibly correlated with low levels of ACE2 expression [44]. IL-13 also reduces ACE2 expression, suggesting that M2-macrophages may contribute to viral resistance. BCG and other immunisations may transiently promote non-specific resistance to SARS-CoV2 [45], to be confirmed in trials. Mononuclear phagocytes are implicated in selected genetic [46] or acquired systemic immunodeficiency, immunosuppression and autoimmunity, including chronic renal disease requiring organ transplantation. Tumor associated macrophages (TAM) and Myeloid derived suppressor cells (MDSC) promote malignancy and metastasis, and with chemo-and radiotherapy may enhance COVID-19 risk. Microglia contribute to neurodegeneration through interaction with neurons in Alzheimer disease, a comorbidity independent of age.\nComorbidities are likely to be multifactorial, and not all display an obvious macrophage link; for example, the ACE2 locus on the X chromosome [47] may contribute to the decreased risk of females [48], but genetic and environmental factors underlying gender, racial and individual disparities remain unclear. Therapeutics for many comorbidities impact on macrophage inflammatory and metabolic functions, including statins, sugar stabilizers, anti-hypertensives and anti-inflammatory agents; control of diabetes and obesity are important in preventing severe infection. Glucocorticoids, which have potent anti-inflammatory effects on macrophages, are contra-indicated in early infection, while protecting against severe disease; timing of administration is therefore critical [49]. The use of anti-TNF antibody in treatment of rheumatoid arthritis, protects against subsequent severe COVID-19 requiring hospitalization [50].\nIn conclusion, the present evidence for a common macrophage contribution to a range of comorbidities is correlative, rather than causal. Nor is it clear whether they increase the risk as well as the severity of infection. Macrophages are central to inflammation, immunity and metabolic diseases, but further genetic and cellular studies are needed to provide a unifying hypothesis.\n\n3.3 Asymptomatic and initial, mild infection\nThere is little direct evidence how monocytes and tissue macrophages contribute to asymptomatic infection, but their tissue distribution, receptor repertoire and secretory capacity are vital to viral resistance as well as dissemination. Acute macrophage antiviral and inflammatory responses determine the outcome of infection, together with other innate and adaptive host mechanisms. We outline evidence from clinical [20] and experimental observations from earlier [51] and current [20] coronavirus studies and consider the role of macrophages and monocytes in local and systemic infections, the antiviral and inflammatory response, resolution and complications.\nMost COVID-19 infections follow droplet inhalation and upper respiratory airway infection, which can be asymptomatic or mild, depending on mucosal immunity and IgA protection. Nasopharyngeal epithelium expresses ACE2 and is an early target for infection. Even if local tissue macrophages do not express ACE2 receptors and are not directly infected, they play a role in inflammatory cytokine responses to infected cells through surface, endosomal and cytosolic receptors and secretion of IL-1 family members [52] and antiviral interferons (IFNs). Monocytes, dendritic cells and tissue macrophages can bind virus through lectin-like receptors such as CD169 [53], for transport to regional lymph nodes. Delivery of virus droplets to the lower respiratory tract leads to infection of ACE2+ alveolar epithelium and capillary endothelium. Detection of intracellular RNA in alveolar macrophages could result from uptake of infected epithelial and endothelial cell debris rather than active infection. Single cell mRNA studies of bronchoalveolar lavage in COVID-19, have confirmed the recruitment of inflammatory monocytes as well as the presence of reactive alveolar macrophages in lung [17,18].\nSeveral common symptoms of early infection can be the indirect result of epithelial cell necrosis by viral infection mediated by ACE2 and/or other co-receptors, such as transmembrane protease serine 2, (TMPRSS2) [13]. Uptake of virus or epithelial cell debris by lung macrophages can initiate inflammasome activation by P2RX7 and release IL-1β, Type1 IFN, IL-6 and TNF [3], contributing to fever, pain, lethargy and headache. Raised levels of C-reactive protein (CRP), induced in hepatocytes by IL-6, are acute phase, plasma biomarkers of COVID-19. Other macrophage products include chemokines such as IL-8 (CXCL8) and MCP-1 (CCL2), recruiting abundant PMN and monocytes to sites of infection. Through viraemia COVID-19 reaches systemic organs such as heart, gut, brain and kidney, which contain resident and recruited macrophage populations; these contribute to local, specialised dysfunctions, such as myocarditis and cardiac arrhythmia, following interactions of macrophages and infected cardiomyocytes [54]. Intravascular coagulation [3,24] promotes dissemination of microthrombi-emboli to lungs, heart and brain, and fibrin degradation d-dimers appear in blood. This is evidence of early resolution, enhanced by the generation of antiviral IgM and IgG.\nWe have little understanding of the innate and adaptive mechanisms that fail to clear local viral infection and at what stage IFN [55,56], other pro-inflammatory [57] and haematopoietic responses become dysregulated in blood monocytes [58]. Together with compromised lung oxygenation, this can lead to systemic immune and vascular dysfunctions. A syndrome of mild infection in younger subjects gives rise to chilblain-like inflammation in toes and fingers [59]. The uncommon multisystem Kawasaki-like inflammatory syndrome of children results from atypical immune responses to COVID-19 [60,61]. This involves anti-viral antibody, systemic vasculitis affecting heart rather than lung, and can respond to corticosteroids. Apart from platelet activation, mononuclear phagocytes are known to produce tissue factor and other procoagulants [62], Factors 5 and 13; fibrinolysis by vascular endothelium and inflammatory macrophages [63] is mediated by secretion of urokinase, which cleaves plasminogen to plasmin; its activity is regulated by inhibitors in plasma, such as alpha2 macroglobulin. Anticoagulants and intranasal or inhaled Type1 IFN may be useful inhibitors of thrombosis and local viral infection, limiting progression to more severe infection.\n\n3.4 Moderate and severe infection: the hyperinflammatory syndrome\nBetween 8–12 days after COVID-19 infection, patients can progress to severe lung infection characterized by pneumonia, increased vascular permeability, edema, and hypoxia, requiring oxygen or mechanical ventilation. This is part of a systemic viral infection of ACE2+epithelia and endothelia, widespread cell death, ischaemia, hypotension and organ failure. Blood analysis at time of hospitalization, has revealed polymorphonuclear leukocytosis, altered levels of abnormal monocytes and lymphopaenia [58,64]. Myeloid cell recruitment to lung contributes to the hyperinflammatory and coagulopathy acute respiratory distress syndrome (ARDS) [20]. This is accompanied by monocyte/macrophage dysregulated production of secretory products. It is not clear which factors contribute to this complication: enhanced viral growth–perhaps triggered by early, poorly neutralizing IgM and complement or IgG, hypoxia and loss of antiviral mechanisms of macrophages–directly or secondary to lymphopaenia, massive local epithelial and endothelial necrosis, hyperactivation of newly recruited immature monocytes, or a “perfect storm” encompassing several of the above. This syndrome could be triggered by induction of ACE2 on specific populations of monocytes and macrophages, resulting in their direct infection. By this stage, spleen and draining nodes at sites of infection are severely disorganized [65]. M1-like monocytes carrying virus through CD169 or other receptors, whether infected or not, can disseminate the virus throughout the body by a Trojan horse mechanism [66]. It is not known whether lymphocytes, not infected, die by apoptosis or necrosis, from products of activated lymphocytes or macrophages such as TNF, or by phagoptosis. We summarize evidence that blood monocytes and activated tissue macrophages contribute to severe COVID-19 and consider virus-induced macrophage pathogenetic mechanisms, which can be targeted therapeutically.\nEarlier studies on SARS1/MERS revealed many of the features of ARDS and of macrophage involvement [6,51]. Initial blood and tissue analysis of COVID-19 provided morphologic evidence of monocyte abnormality and intense macrophage phagocytic activity in infected organs [65]. FACS and single cell RNA analysis of monocytes and broncho-alveolar macrophages [18] provided evidence of emergency myelopoiesis [64] and confirmed the presence of recruited and activated macrophages in alveoli [17] and lung interstitium. Plasma membrane opsonic and other receptors contribute to dysregulated inflammation, monocytic hyperactivation and impaired phagocytic clearance of apoptotic and necrotic cells and debris. Acting through NFkB, RNA, DNA and other sensing and signaling pathways, they initiate production of numerous secretory products. Particular antiviral and proinflammatory products have been targeted for anti-inflammatory treatment, including the IFNs [55,56], IL-1 family [52], IL-6 [27] and TNF [22]. In addition, mononuclear phagocytes interact with plasma cascades, and through upregulated adhesion molecules, with other myeloid and lymphoid cells, platelets, system-wide endothelia and epithelia.\nDysregulated activation of macrophages contributes to the hyperinflammatory and thrombotic pathways of severe COVID-19 [3,24,67].Virus-induced cell injury, apoptosis, necrosis and necroptosis are sensed by distinct, opposing macrophage receptor-dependent effector responses. These include activating and inhibitory pathways of IL-1 production, processing and secretion [52,57], triggered by tissue injury, inflammasome and caspase activation. A highly impaired type1 IFN response, characterized by no IFNβ and low IFNα production and activity, has been associated with persistent viraemia and an exacerbated inflammatory response, partially driven by NFkB, TNF and IL-6 [56]. Endogenous oxidized phospholipids reprogramme macrophage metabolism and boost hyperinflammation [68]. By capturing inflammatory lipids released from dying cells, CD14 induces inflammasome-dependent phagocyte hyperactivation [69]. Macrophage fuel production and utilization [36] are sensitive to hypoxia, HIF-1 responses [70] and iron availability, influencing M1 polarization and effector functions. Activated macrophages trigger coagulation and complement cascades, as well as angiotensin and bradykinin pathways that dysregulate vascular tone and permeability, exacerbating inflammation and edema.\nImmunological processes that may contribute to the outcome of macrophage- viral induced pathology include antibody enhancement of infection (ADE) and inflammation (ADI), and neutrophil NETosis. Anti-spike antiserum can induce hyperinflammation via macrophage FcR, depending on IgG glycosylation and Syk involvement [71]. Cross-reacting antibodies from previous benign coronavirus infections also contribute to enhanced pathology [72]. Dendritic cell dysfunction, ascribed to down regulated HLA-DR expression [67,72] and defective antigen presentation to T and B lymphocytes, may result from lack of costimulatory signals, aborting lymphocyte proliferation and activation and mediating widespread clonal death. Haemophagocytosis, a feature of the macrophage activation syndrome (MAS), is also observed in other viral infections.\n\n3.5 Recovery\nMacrophages are central to the cellular processes which contribute to recovery from COVID-19 infection; they remove debris and necrotic tissue through phagocytosis and secretion of elastase and collagenase, and produce IGF1 and TGF-β to promote tissue recovery. M2-like macrophages are the source of potent lipid metabolites which resolve inflammation; these include resolvins, protectins and maresins, short lived autacoids which regulate the magnitude and duration of acute inflammation [25,73]. Acting through macrophage GPCRs for these metabolites, they enhance efferocytosis of dying neutrophils, and counter inflammation without immunosuppression.\nRecovery can be prolonged after severe infection, involving fever, lethargy, scarring and loss of organ function. Italiani and colleagues profiled the course of resolving versus persistent inflammation with special reference to IL-1 family molecules [57]. An independent single cell mRNA analysis of peripheral blood mononuclear cells during early recovery of COVID-19 infection [23], revealed an increased ratio and level of classical CD14++IL-1β+ monocytes. Further studies are needed to compare monocytes and tissue macrophages after mild or severe infection and to establish whether repolarisation of macrophages from M1 to an M2 phenotype can promote resolution and recovery after COVID-19. After helminth infection, M2 macrophages express resistin, which protects against LPS-induced toxic shock [74]. New or repurposed therapies may be able to modify the sequelae of severe infection."}

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This natural timing should be used to establish key point-of-care sampling timepoints, avoiding patient discomfort and to focus resources. Infection can progress or be aborted at every stage, presenting a dynamic continuum, to which macrophages and monocytes contribute, together with other immune and non-immune elements; MPS contributions to COVID-19 resistance and pathogenesis are still underestimated and poorly understood.\nFig. 2 Decision points that determine the outcome of COVID-19 infection and requirements for a monocyte activation assay. A time and severity pattern has emerged for COVID-19 progression. The first days, first and second week timelines are turning points for resolution or deterioration. Epidemiologic precision for these milestones and precise parameters will be valuable for strategic sampling and patient stratification, sparing resources and patient material. With limited volumes of peripheral blood, a window on progression of the infection can be obtained by studying activation of the mononuclear phagocyte system, largely represented by monocytes in blood. The cells are biosynthetically active and relatively long lived, ideal to trace long term effects of comorbidities and infection. We highlight selected functional categories that should be addressed in monocytes and can be adapted to particular applications.\n\n3.2 Co-morbidities and the mps\nMacrophage activities contribute to many co- morbidities [8,9], including aging [28], obesity [29], diabetes [30], exposure to pollutants [31], and microbiome properties [32]. Macrophage functions alter with age, together with adaptive immune processes such as thymic involution, which deplete T lymphocyte reserves. Chronic, low grade inflammation (INFLAMMAGING) has been proposed as a predisposing factor [33]. This may result from failure of macrophages and NK cells to clear increasing accumulation of senescent cells, that enhance basal levels of inflammation and interfere with subsequent adaptive immunity upon infection [28]. Baseline inflammation may not be detrimental in itself, but can initiate an inflammatory cascade that amplifies excessive inflammation occurring in response to pathogens. Age-related metabolic correlates of macrophage dysfunction include innate lymphoid cell interactions with adipose tissue and associated macrophages, as well as inflammasome activation [34,35]. This affects thermogenesis, part of a wider metabolic syndrome involving glucose and lipid metabolism [36], elevated body mass index (BMI), type 1 and type 2 diabetes, obesity and atherosclerosis [37]. These correlate with macrophage metabolic and mitochondrial activities [38] and, possibly, ACE2 expression and hypertension, another co-morbidity [37]. ACE2, the COVID-19 entry receptor, is widely expressed on microvascular endothelium and binds the SARS-CoV2 spike glycoprotein implicated in angiotensin regulation by its competition with ACE1, and potential role as an anti-inflammatory agent [39]. Macrophages in tuberculosis and sarcoidosis express ACE1 [40], but expression of ACE2 by monocytes and tissue macrophages has not been validated [41]; evidence for productive infection of macrophages via ACE2 is incomplete [15]. Macrophages express scavenger receptors including Axl and MERTK, tyrosine kinase receptors implicated in phosphatidyl serine recognition and phagocytosis of apoptotic cells [21]; Axl is a coreceptor for ACE2+ dependent infection of other cell types by COVID-19 and other enveloped viruses via surface or endocytic routes [42], the basis for a clinical trial involving an Axl inhibitor.\nAlveolar macrophages [43] are close to Type 1 pneumocytes, involved in gas exchange, Type 2 surfactant-producing pneumocytes, and capillary endothelium, all ACE 2+ [43]. They take up and store atmospheric pollutants and poorly-degradable pro-inflammatory particles; host DNA from dying cells can induce the innate STING pathway after uptake and also activate inflammasomes in lung macrophages after exposure to ozone and cigarette smoke [31]. Other airway predisposing conditions involving macrophages [8,9], include genetic disorders such as fibrocystic disease and structural abnormalities associated with chronic inflammation and infection.\nChronic infections in which TH1-activated macrophages play a major role, tuberculosis and AIDS, enhance the risk of severe infection, with odds ratios of 1.7 and 2.3– respectively. TH2-dependent asthma may not enhance COVID-19 susceptibility, possibly correlated with low levels of ACE2 expression [44]. IL-13 also reduces ACE2 expression, suggesting that M2-macrophages may contribute to viral resistance. BCG and other immunisations may transiently promote non-specific resistance to SARS-CoV2 [45], to be confirmed in trials. Mononuclear phagocytes are implicated in selected genetic [46] or acquired systemic immunodeficiency, immunosuppression and autoimmunity, including chronic renal disease requiring organ transplantation. Tumor associated macrophages (TAM) and Myeloid derived suppressor cells (MDSC) promote malignancy and metastasis, and with chemo-and radiotherapy may enhance COVID-19 risk. Microglia contribute to neurodegeneration through interaction with neurons in Alzheimer disease, a comorbidity independent of age.\nComorbidities are likely to be multifactorial, and not all display an obvious macrophage link; for example, the ACE2 locus on the X chromosome [47] may contribute to the decreased risk of females [48], but genetic and environmental factors underlying gender, racial and individual disparities remain unclear. Therapeutics for many comorbidities impact on macrophage inflammatory and metabolic functions, including statins, sugar stabilizers, anti-hypertensives and anti-inflammatory agents; control of diabetes and obesity are important in preventing severe infection. Glucocorticoids, which have potent anti-inflammatory effects on macrophages, are contra-indicated in early infection, while protecting against severe disease; timing of administration is therefore critical [49]. The use of anti-TNF antibody in treatment of rheumatoid arthritis, protects against subsequent severe COVID-19 requiring hospitalization [50].\nIn conclusion, the present evidence for a common macrophage contribution to a range of comorbidities is correlative, rather than causal. Nor is it clear whether they increase the risk as well as the severity of infection. Macrophages are central to inflammation, immunity and metabolic diseases, but further genetic and cellular studies are needed to provide a unifying hypothesis.\n\n3.3 Asymptomatic and initial, mild infection\nThere is little direct evidence how monocytes and tissue macrophages contribute to asymptomatic infection, but their tissue distribution, receptor repertoire and secretory capacity are vital to viral resistance as well as dissemination. Acute macrophage antiviral and inflammatory responses determine the outcome of infection, together with other innate and adaptive host mechanisms. We outline evidence from clinical [20] and experimental observations from earlier [51] and current [20] coronavirus studies and consider the role of macrophages and monocytes in local and systemic infections, the antiviral and inflammatory response, resolution and complications.\nMost COVID-19 infections follow droplet inhalation and upper respiratory airway infection, which can be asymptomatic or mild, depending on mucosal immunity and IgA protection. Nasopharyngeal epithelium expresses ACE2 and is an early target for infection. Even if local tissue macrophages do not express ACE2 receptors and are not directly infected, they play a role in inflammatory cytokine responses to infected cells through surface, endosomal and cytosolic receptors and secretion of IL-1 family members [52] and antiviral interferons (IFNs). Monocytes, dendritic cells and tissue macrophages can bind virus through lectin-like receptors such as CD169 [53], for transport to regional lymph nodes. Delivery of virus droplets to the lower respiratory tract leads to infection of ACE2+ alveolar epithelium and capillary endothelium. Detection of intracellular RNA in alveolar macrophages could result from uptake of infected epithelial and endothelial cell debris rather than active infection. Single cell mRNA studies of bronchoalveolar lavage in COVID-19, have confirmed the recruitment of inflammatory monocytes as well as the presence of reactive alveolar macrophages in lung [17,18].\nSeveral common symptoms of early infection can be the indirect result of epithelial cell necrosis by viral infection mediated by ACE2 and/or other co-receptors, such as transmembrane protease serine 2, (TMPRSS2) [13]. Uptake of virus or epithelial cell debris by lung macrophages can initiate inflammasome activation by P2RX7 and release IL-1β, Type1 IFN, IL-6 and TNF [3], contributing to fever, pain, lethargy and headache. Raised levels of C-reactive protein (CRP), induced in hepatocytes by IL-6, are acute phase, plasma biomarkers of COVID-19. Other macrophage products include chemokines such as IL-8 (CXCL8) and MCP-1 (CCL2), recruiting abundant PMN and monocytes to sites of infection. Through viraemia COVID-19 reaches systemic organs such as heart, gut, brain and kidney, which contain resident and recruited macrophage populations; these contribute to local, specialised dysfunctions, such as myocarditis and cardiac arrhythmia, following interactions of macrophages and infected cardiomyocytes [54]. Intravascular coagulation [3,24] promotes dissemination of microthrombi-emboli to lungs, heart and brain, and fibrin degradation d-dimers appear in blood. This is evidence of early resolution, enhanced by the generation of antiviral IgM and IgG.\nWe have little understanding of the innate and adaptive mechanisms that fail to clear local viral infection and at what stage IFN [55,56], other pro-inflammatory [57] and haematopoietic responses become dysregulated in blood monocytes [58]. Together with compromised lung oxygenation, this can lead to systemic immune and vascular dysfunctions. A syndrome of mild infection in younger subjects gives rise to chilblain-like inflammation in toes and fingers [59]. The uncommon multisystem Kawasaki-like inflammatory syndrome of children results from atypical immune responses to COVID-19 [60,61]. This involves anti-viral antibody, systemic vasculitis affecting heart rather than lung, and can respond to corticosteroids. Apart from platelet activation, mononuclear phagocytes are known to produce tissue factor and other procoagulants [62], Factors 5 and 13; fibrinolysis by vascular endothelium and inflammatory macrophages [63] is mediated by secretion of urokinase, which cleaves plasminogen to plasmin; its activity is regulated by inhibitors in plasma, such as alpha2 macroglobulin. Anticoagulants and intranasal or inhaled Type1 IFN may be useful inhibitors of thrombosis and local viral infection, limiting progression to more severe infection.\n\n3.4 Moderate and severe infection: the hyperinflammatory syndrome\nBetween 8–12 days after COVID-19 infection, patients can progress to severe lung infection characterized by pneumonia, increased vascular permeability, edema, and hypoxia, requiring oxygen or mechanical ventilation. This is part of a systemic viral infection of ACE2+epithelia and endothelia, widespread cell death, ischaemia, hypotension and organ failure. Blood analysis at time of hospitalization, has revealed polymorphonuclear leukocytosis, altered levels of abnormal monocytes and lymphopaenia [58,64]. Myeloid cell recruitment to lung contributes to the hyperinflammatory and coagulopathy acute respiratory distress syndrome (ARDS) [20]. This is accompanied by monocyte/macrophage dysregulated production of secretory products. It is not clear which factors contribute to this complication: enhanced viral growth–perhaps triggered by early, poorly neutralizing IgM and complement or IgG, hypoxia and loss of antiviral mechanisms of macrophages–directly or secondary to lymphopaenia, massive local epithelial and endothelial necrosis, hyperactivation of newly recruited immature monocytes, or a “perfect storm” encompassing several of the above. This syndrome could be triggered by induction of ACE2 on specific populations of monocytes and macrophages, resulting in their direct infection. By this stage, spleen and draining nodes at sites of infection are severely disorganized [65]. M1-like monocytes carrying virus through CD169 or other receptors, whether infected or not, can disseminate the virus throughout the body by a Trojan horse mechanism [66]. It is not known whether lymphocytes, not infected, die by apoptosis or necrosis, from products of activated lymphocytes or macrophages such as TNF, or by phagoptosis. We summarize evidence that blood monocytes and activated tissue macrophages contribute to severe COVID-19 and consider virus-induced macrophage pathogenetic mechanisms, which can be targeted therapeutically.\nEarlier studies on SARS1/MERS revealed many of the features of ARDS and of macrophage involvement [6,51]. Initial blood and tissue analysis of COVID-19 provided morphologic evidence of monocyte abnormality and intense macrophage phagocytic activity in infected organs [65]. FACS and single cell RNA analysis of monocytes and broncho-alveolar macrophages [18] provided evidence of emergency myelopoiesis [64] and confirmed the presence of recruited and activated macrophages in alveoli [17] and lung interstitium. Plasma membrane opsonic and other receptors contribute to dysregulated inflammation, monocytic hyperactivation and impaired phagocytic clearance of apoptotic and necrotic cells and debris. Acting through NFkB, RNA, DNA and other sensing and signaling pathways, they initiate production of numerous secretory products. Particular antiviral and proinflammatory products have been targeted for anti-inflammatory treatment, including the IFNs [55,56], IL-1 family [52], IL-6 [27] and TNF [22]. In addition, mononuclear phagocytes interact with plasma cascades, and through upregulated adhesion molecules, with other myeloid and lymphoid cells, platelets, system-wide endothelia and epithelia.\nDysregulated activation of macrophages contributes to the hyperinflammatory and thrombotic pathways of severe COVID-19 [3,24,67].Virus-induced cell injury, apoptosis, necrosis and necroptosis are sensed by distinct, opposing macrophage receptor-dependent effector responses. These include activating and inhibitory pathways of IL-1 production, processing and secretion [52,57], triggered by tissue injury, inflammasome and caspase activation. A highly impaired type1 IFN response, characterized by no IFNβ and low IFNα production and activity, has been associated with persistent viraemia and an exacerbated inflammatory response, partially driven by NFkB, TNF and IL-6 [56]. Endogenous oxidized phospholipids reprogramme macrophage metabolism and boost hyperinflammation [68]. By capturing inflammatory lipids released from dying cells, CD14 induces inflammasome-dependent phagocyte hyperactivation [69]. Macrophage fuel production and utilization [36] are sensitive to hypoxia, HIF-1 responses [70] and iron availability, influencing M1 polarization and effector functions. Activated macrophages trigger coagulation and complement cascades, as well as angiotensin and bradykinin pathways that dysregulate vascular tone and permeability, exacerbating inflammation and edema.\nImmunological processes that may contribute to the outcome of macrophage- viral induced pathology include antibody enhancement of infection (ADE) and inflammation (ADI), and neutrophil NETosis. Anti-spike antiserum can induce hyperinflammation via macrophage FcR, depending on IgG glycosylation and Syk involvement [71]. Cross-reacting antibodies from previous benign coronavirus infections also contribute to enhanced pathology [72]. Dendritic cell dysfunction, ascribed to down regulated HLA-DR expression [67,72] and defective antigen presentation to T and B lymphocytes, may result from lack of costimulatory signals, aborting lymphocyte proliferation and activation and mediating widespread clonal death. Haemophagocytosis, a feature of the macrophage activation syndrome (MAS), is also observed in other viral infections.\n\n3.5 Recovery\nMacrophages are central to the cellular processes which contribute to recovery from COVID-19 infection; they remove debris and necrotic tissue through phagocytosis and secretion of elastase and collagenase, and produce IGF1 and TGF-β to promote tissue recovery. M2-like macrophages are the source of potent lipid metabolites which resolve inflammation; these include resolvins, protectins and maresins, short lived autacoids which regulate the magnitude and duration of acute inflammation [25,73]. Acting through macrophage GPCRs for these metabolites, they enhance efferocytosis of dying neutrophils, and counter inflammation without immunosuppression.\nRecovery can be prolonged after severe infection, involving fever, lethargy, scarring and loss of organ function. Italiani and colleagues profiled the course of resolving versus persistent inflammation with special reference to IL-1 family molecules [57]. An independent single cell mRNA analysis of peripheral blood mononuclear cells during early recovery of COVID-19 infection [23], revealed an increased ratio and level of classical CD14++IL-1β+ monocytes. Further studies are needed to compare monocytes and tissue macrophages after mild or severe infection and to establish whether repolarisation of macrophages from M1 to an M2 phenotype can promote resolution and recovery after COVID-19. After helminth infection, M2 macrophages express resistin, which protects against LPS-induced toxic shock [74]. 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COVID-19 infection\n3.1 It is customary to divide the course of the infection into different stages: Preinfection (co-morbidities), asymptomatic, early clinical, severe clinical (acute respiratory distress syndrome–ARDS), and recovery [8,9], Fig. 2 . This natural timing should be used to establish key point-of-care sampling timepoints, avoiding patient discomfort and to focus resources. Infection can progress or be aborted at every stage, presenting a dynamic continuum, to which macrophages and monocytes contribute, together with other immune and non-immune elements; MPS contributions to COVID-19 resistance and pathogenesis are still underestimated and poorly understood.\nFig. 2 Decision points that determine the outcome of COVID-19 infection and requirements for a monocyte activation assay. A time and severity pattern has emerged for COVID-19 progression. The first days, first and second week timelines are turning points for resolution or deterioration. Epidemiologic precision for these milestones and precise parameters will be valuable for strategic sampling and patient stratification, sparing resources and patient material. With limited volumes of peripheral blood, a window on progression of the infection can be obtained by studying activation of the mononuclear phagocyte system, largely represented by monocytes in blood. The cells are biosynthetically active and relatively long lived, ideal to trace long term effects of comorbidities and infection. We highlight selected functional categories that should be addressed in monocytes and can be adapted to particular applications.\n\n3.2 Co-morbidities and the mps\nMacrophage activities contribute to many co- morbidities [8,9], including aging [28], obesity [29], diabetes [30], exposure to pollutants [31], and microbiome properties [32]. Macrophage functions alter with age, together with adaptive immune processes such as thymic involution, which deplete T lymphocyte reserves. Chronic, low grade inflammation (INFLAMMAGING) has been proposed as a predisposing factor [33]. This may result from failure of macrophages and NK cells to clear increasing accumulation of senescent cells, that enhance basal levels of inflammation and interfere with subsequent adaptive immunity upon infection [28]. Baseline inflammation may not be detrimental in itself, but can initiate an inflammatory cascade that amplifies excessive inflammation occurring in response to pathogens. Age-related metabolic correlates of macrophage dysfunction include innate lymphoid cell interactions with adipose tissue and associated macrophages, as well as inflammasome activation [34,35]. This affects thermogenesis, part of a wider metabolic syndrome involving glucose and lipid metabolism [36], elevated body mass index (BMI), type 1 and type 2 diabetes, obesity and atherosclerosis [37]. These correlate with macrophage metabolic and mitochondrial activities [38] and, possibly, ACE2 expression and hypertension, another co-morbidity [37]. ACE2, the COVID-19 entry receptor, is widely expressed on microvascular endothelium and binds the SARS-CoV2 spike glycoprotein implicated in angiotensin regulation by its competition with ACE1, and potential role as an anti-inflammatory agent [39]. Macrophages in tuberculosis and sarcoidosis express ACE1 [40], but expression of ACE2 by monocytes and tissue macrophages has not been validated [41]; evidence for productive infection of macrophages via ACE2 is incomplete [15]. Macrophages express scavenger receptors including Axl and MERTK, tyrosine kinase receptors implicated in phosphatidyl serine recognition and phagocytosis of apoptotic cells [21]; Axl is a coreceptor for ACE2+ dependent infection of other cell types by COVID-19 and other enveloped viruses via surface or endocytic routes [42], the basis for a clinical trial involving an Axl inhibitor.\nAlveolar macrophages [43] are close to Type 1 pneumocytes, involved in gas exchange, Type 2 surfactant-producing pneumocytes, and capillary endothelium, all ACE 2+ [43]. They take up and store atmospheric pollutants and poorly-degradable pro-inflammatory particles; host DNA from dying cells can induce the innate STING pathway after uptake and also activate inflammasomes in lung macrophages after exposure to ozone and cigarette smoke [31]. Other airway predisposing conditions involving macrophages [8,9], include genetic disorders such as fibrocystic disease and structural abnormalities associated with chronic inflammation and infection.\nChronic infections in which TH1-activated macrophages play a major role, tuberculosis and AIDS, enhance the risk of severe infection, with odds ratios of 1.7 and 2.3– respectively. TH2-dependent asthma may not enhance COVID-19 susceptibility, possibly correlated with low levels of ACE2 expression [44]. IL-13 also reduces ACE2 expression, suggesting that M2-macrophages may contribute to viral resistance. BCG and other immunisations may transiently promote non-specific resistance to SARS-CoV2 [45], to be confirmed in trials. Mononuclear phagocytes are implicated in selected genetic [46] or acquired systemic immunodeficiency, immunosuppression and autoimmunity, including chronic renal disease requiring organ transplantation. Tumor associated macrophages (TAM) and Myeloid derived suppressor cells (MDSC) promote malignancy and metastasis, and with chemo-and radiotherapy may enhance COVID-19 risk. Microglia contribute to neurodegeneration through interaction with neurons in Alzheimer disease, a comorbidity independent of age.\nComorbidities are likely to be multifactorial, and not all display an obvious macrophage link; for example, the ACE2 locus on the X chromosome [47] may contribute to the decreased risk of females [48], but genetic and environmental factors underlying gender, racial and individual disparities remain unclear. Therapeutics for many comorbidities impact on macrophage inflammatory and metabolic functions, including statins, sugar stabilizers, anti-hypertensives and anti-inflammatory agents; control of diabetes and obesity are important in preventing severe infection. Glucocorticoids, which have potent anti-inflammatory effects on macrophages, are contra-indicated in early infection, while protecting against severe disease; timing of administration is therefore critical [49]. The use of anti-TNF antibody in treatment of rheumatoid arthritis, protects against subsequent severe COVID-19 requiring hospitalization [50].\nIn conclusion, the present evidence for a common macrophage contribution to a range of comorbidities is correlative, rather than causal. Nor is it clear whether they increase the risk as well as the severity of infection. Macrophages are central to inflammation, immunity and metabolic diseases, but further genetic and cellular studies are needed to provide a unifying hypothesis.\n\n3.3 Asymptomatic and initial, mild infection\nThere is little direct evidence how monocytes and tissue macrophages contribute to asymptomatic infection, but their tissue distribution, receptor repertoire and secretory capacity are vital to viral resistance as well as dissemination. Acute macrophage antiviral and inflammatory responses determine the outcome of infection, together with other innate and adaptive host mechanisms. We outline evidence from clinical [20] and experimental observations from earlier [51] and current [20] coronavirus studies and consider the role of macrophages and monocytes in local and systemic infections, the antiviral and inflammatory response, resolution and complications.\nMost COVID-19 infections follow droplet inhalation and upper respiratory airway infection, which can be asymptomatic or mild, depending on mucosal immunity and IgA protection. Nasopharyngeal epithelium expresses ACE2 and is an early target for infection. Even if local tissue macrophages do not express ACE2 receptors and are not directly infected, they play a role in inflammatory cytokine responses to infected cells through surface, endosomal and cytosolic receptors and secretion of IL-1 family members [52] and antiviral interferons (IFNs). Monocytes, dendritic cells and tissue macrophages can bind virus through lectin-like receptors such as CD169 [53], for transport to regional lymph nodes. Delivery of virus droplets to the lower respiratory tract leads to infection of ACE2+ alveolar epithelium and capillary endothelium. Detection of intracellular RNA in alveolar macrophages could result from uptake of infected epithelial and endothelial cell debris rather than active infection. Single cell mRNA studies of bronchoalveolar lavage in COVID-19, have confirmed the recruitment of inflammatory monocytes as well as the presence of reactive alveolar macrophages in lung [17,18].\nSeveral common symptoms of early infection can be the indirect result of epithelial cell necrosis by viral infection mediated by ACE2 and/or other co-receptors, such as transmembrane protease serine 2, (TMPRSS2) [13]. Uptake of virus or epithelial cell debris by lung macrophages can initiate inflammasome activation by P2RX7 and release IL-1β, Type1 IFN, IL-6 and TNF [3], contributing to fever, pain, lethargy and headache. Raised levels of C-reactive protein (CRP), induced in hepatocytes by IL-6, are acute phase, plasma biomarkers of COVID-19. Other macrophage products include chemokines such as IL-8 (CXCL8) and MCP-1 (CCL2), recruiting abundant PMN and monocytes to sites of infection. Through viraemia COVID-19 reaches systemic organs such as heart, gut, brain and kidney, which contain resident and recruited macrophage populations; these contribute to local, specialised dysfunctions, such as myocarditis and cardiac arrhythmia, following interactions of macrophages and infected cardiomyocytes [54]. Intravascular coagulation [3,24] promotes dissemination of microthrombi-emboli to lungs, heart and brain, and fibrin degradation d-dimers appear in blood. This is evidence of early resolution, enhanced by the generation of antiviral IgM and IgG.\nWe have little understanding of the innate and adaptive mechanisms that fail to clear local viral infection and at what stage IFN [55,56], other pro-inflammatory [57] and haematopoietic responses become dysregulated in blood monocytes [58]. Together with compromised lung oxygenation, this can lead to systemic immune and vascular dysfunctions. A syndrome of mild infection in younger subjects gives rise to chilblain-like inflammation in toes and fingers [59]. The uncommon multisystem Kawasaki-like inflammatory syndrome of children results from atypical immune responses to COVID-19 [60,61]. This involves anti-viral antibody, systemic vasculitis affecting heart rather than lung, and can respond to corticosteroids. Apart from platelet activation, mononuclear phagocytes are known to produce tissue factor and other procoagulants [62], Factors 5 and 13; fibrinolysis by vascular endothelium and inflammatory macrophages [63] is mediated by secretion of urokinase, which cleaves plasminogen to plasmin; its activity is regulated by inhibitors in plasma, such as alpha2 macroglobulin. Anticoagulants and intranasal or inhaled Type1 IFN may be useful inhibitors of thrombosis and local viral infection, limiting progression to more severe infection.\n\n3.4 Moderate and severe infection: the hyperinflammatory syndrome\nBetween 8–12 days after COVID-19 infection, patients can progress to severe lung infection characterized by pneumonia, increased vascular permeability, edema, and hypoxia, requiring oxygen or mechanical ventilation. This is part of a systemic viral infection of ACE2+epithelia and endothelia, widespread cell death, ischaemia, hypotension and organ failure. Blood analysis at time of hospitalization, has revealed polymorphonuclear leukocytosis, altered levels of abnormal monocytes and lymphopaenia [58,64]. Myeloid cell recruitment to lung contributes to the hyperinflammatory and coagulopathy acute respiratory distress syndrome (ARDS) [20]. This is accompanied by monocyte/macrophage dysregulated production of secretory products. It is not clear which factors contribute to this complication: enhanced viral growth–perhaps triggered by early, poorly neutralizing IgM and complement or IgG, hypoxia and loss of antiviral mechanisms of macrophages–directly or secondary to lymphopaenia, massive local epithelial and endothelial necrosis, hyperactivation of newly recruited immature monocytes, or a “perfect storm” encompassing several of the above. This syndrome could be triggered by induction of ACE2 on specific populations of monocytes and macrophages, resulting in their direct infection. By this stage, spleen and draining nodes at sites of infection are severely disorganized [65]. M1-like monocytes carrying virus through CD169 or other receptors, whether infected or not, can disseminate the virus throughout the body by a Trojan horse mechanism [66]. It is not known whether lymphocytes, not infected, die by apoptosis or necrosis, from products of activated lymphocytes or macrophages such as TNF, or by phagoptosis. We summarize evidence that blood monocytes and activated tissue macrophages contribute to severe COVID-19 and consider virus-induced macrophage pathogenetic mechanisms, which can be targeted therapeutically.\nEarlier studies on SARS1/MERS revealed many of the features of ARDS and of macrophage involvement [6,51]. Initial blood and tissue analysis of COVID-19 provided morphologic evidence of monocyte abnormality and intense macrophage phagocytic activity in infected organs [65]. FACS and single cell RNA analysis of monocytes and broncho-alveolar macrophages [18] provided evidence of emergency myelopoiesis [64] and confirmed the presence of recruited and activated macrophages in alveoli [17] and lung interstitium. Plasma membrane opsonic and other receptors contribute to dysregulated inflammation, monocytic hyperactivation and impaired phagocytic clearance of apoptotic and necrotic cells and debris. Acting through NFkB, RNA, DNA and other sensing and signaling pathways, they initiate production of numerous secretory products. Particular antiviral and proinflammatory products have been targeted for anti-inflammatory treatment, including the IFNs [55,56], IL-1 family [52], IL-6 [27] and TNF [22]. In addition, mononuclear phagocytes interact with plasma cascades, and through upregulated adhesion molecules, with other myeloid and lymphoid cells, platelets, system-wide endothelia and epithelia.\nDysregulated activation of macrophages contributes to the hyperinflammatory and thrombotic pathways of severe COVID-19 [3,24,67].Virus-induced cell injury, apoptosis, necrosis and necroptosis are sensed by distinct, opposing macrophage receptor-dependent effector responses. These include activating and inhibitory pathways of IL-1 production, processing and secretion [52,57], triggered by tissue injury, inflammasome and caspase activation. A highly impaired type1 IFN response, characterized by no IFNβ and low IFNα production and activity, has been associated with persistent viraemia and an exacerbated inflammatory response, partially driven by NFkB, TNF and IL-6 [56]. Endogenous oxidized phospholipids reprogramme macrophage metabolism and boost hyperinflammation [68]. By capturing inflammatory lipids released from dying cells, CD14 induces inflammasome-dependent phagocyte hyperactivation [69]. Macrophage fuel production and utilization [36] are sensitive to hypoxia, HIF-1 responses [70] and iron availability, influencing M1 polarization and effector functions. Activated macrophages trigger coagulation and complement cascades, as well as angiotensin and bradykinin pathways that dysregulate vascular tone and permeability, exacerbating inflammation and edema.\nImmunological processes that may contribute to the outcome of macrophage- viral induced pathology include antibody enhancement of infection (ADE) and inflammation (ADI), and neutrophil NETosis. Anti-spike antiserum can induce hyperinflammation via macrophage FcR, depending on IgG glycosylation and Syk involvement [71]. Cross-reacting antibodies from previous benign coronavirus infections also contribute to enhanced pathology [72]. Dendritic cell dysfunction, ascribed to down regulated HLA-DR expression [67,72] and defective antigen presentation to T and B lymphocytes, may result from lack of costimulatory signals, aborting lymphocyte proliferation and activation and mediating widespread clonal death. Haemophagocytosis, a feature of the macrophage activation syndrome (MAS), is also observed in other viral infections.\n\n3.5 Recovery\nMacrophages are central to the cellular processes which contribute to recovery from COVID-19 infection; they remove debris and necrotic tissue through phagocytosis and secretion of elastase and collagenase, and produce IGF1 and TGF-β to promote tissue recovery. M2-like macrophages are the source of potent lipid metabolites which resolve inflammation; these include resolvins, protectins and maresins, short lived autacoids which regulate the magnitude and duration of acute inflammation [25,73]. Acting through macrophage GPCRs for these metabolites, they enhance efferocytosis of dying neutrophils, and counter inflammation without immunosuppression.\nRecovery can be prolonged after severe infection, involving fever, lethargy, scarring and loss of organ function. Italiani and colleagues profiled the course of resolving versus persistent inflammation with special reference to IL-1 family molecules [57]. An independent single cell mRNA analysis of peripheral blood mononuclear cells during early recovery of COVID-19 infection [23], revealed an increased ratio and level of classical CD14++IL-1β+ monocytes. Further studies are needed to compare monocytes and tissue macrophages after mild or severe infection and to establish whether repolarisation of macrophages from M1 to an M2 phenotype can promote resolution and recovery after COVID-19. After helminth infection, M2 macrophages express resistin, which protects against LPS-induced toxic shock [74]. 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COVID-19 infection\n3.1 It is customary to divide the course of the infection into different stages: Preinfection (co-morbidities), asymptomatic, early clinical, severe clinical (acute respiratory distress syndrome–ARDS), and recovery [8,9], Fig. 2 . This natural timing should be used to establish key point-of-care sampling timepoints, avoiding patient discomfort and to focus resources. Infection can progress or be aborted at every stage, presenting a dynamic continuum, to which macrophages and monocytes contribute, together with other immune and non-immune elements; MPS contributions to COVID-19 resistance and pathogenesis are still underestimated and poorly understood.\nFig. 2 Decision points that determine the outcome of COVID-19 infection and requirements for a monocyte activation assay. A time and severity pattern has emerged for COVID-19 progression. The first days, first and second week timelines are turning points for resolution or deterioration. Epidemiologic precision for these milestones and precise parameters will be valuable for strategic sampling and patient stratification, sparing resources and patient material. With limited volumes of peripheral blood, a window on progression of the infection can be obtained by studying activation of the mononuclear phagocyte system, largely represented by monocytes in blood. The cells are biosynthetically active and relatively long lived, ideal to trace long term effects of comorbidities and infection. We highlight selected functional categories that should be addressed in monocytes and can be adapted to particular applications.\n\n3.2 Co-morbidities and the mps\nMacrophage activities contribute to many co- morbidities [8,9], including aging [28], obesity [29], diabetes [30], exposure to pollutants [31], and microbiome properties [32]. Macrophage functions alter with age, together with adaptive immune processes such as thymic involution, which deplete T lymphocyte reserves. Chronic, low grade inflammation (INFLAMMAGING) has been proposed as a predisposing factor [33]. This may result from failure of macrophages and NK cells to clear increasing accumulation of senescent cells, that enhance basal levels of inflammation and interfere with subsequent adaptive immunity upon infection [28]. Baseline inflammation may not be detrimental in itself, but can initiate an inflammatory cascade that amplifies excessive inflammation occurring in response to pathogens. Age-related metabolic correlates of macrophage dysfunction include innate lymphoid cell interactions with adipose tissue and associated macrophages, as well as inflammasome activation [34,35]. This affects thermogenesis, part of a wider metabolic syndrome involving glucose and lipid metabolism [36], elevated body mass index (BMI), type 1 and type 2 diabetes, obesity and atherosclerosis [37]. These correlate with macrophage metabolic and mitochondrial activities [38] and, possibly, ACE2 expression and hypertension, another co-morbidity [37]. ACE2, the COVID-19 entry receptor, is widely expressed on microvascular endothelium and binds the SARS-CoV2 spike glycoprotein implicated in angiotensin regulation by its competition with ACE1, and potential role as an anti-inflammatory agent [39]. Macrophages in tuberculosis and sarcoidosis express ACE1 [40], but expression of ACE2 by monocytes and tissue macrophages has not been validated [41]; evidence for productive infection of macrophages via ACE2 is incomplete [15]. Macrophages express scavenger receptors including Axl and MERTK, tyrosine kinase receptors implicated in phosphatidyl serine recognition and phagocytosis of apoptotic cells [21]; Axl is a coreceptor for ACE2+ dependent infection of other cell types by COVID-19 and other enveloped viruses via surface or endocytic routes [42], the basis for a clinical trial involving an Axl inhibitor.\nAlveolar macrophages [43] are close to Type 1 pneumocytes, involved in gas exchange, Type 2 surfactant-producing pneumocytes, and capillary endothelium, all ACE 2+ [43]. They take up and store atmospheric pollutants and poorly-degradable pro-inflammatory particles; host DNA from dying cells can induce the innate STING pathway after uptake and also activate inflammasomes in lung macrophages after exposure to ozone and cigarette smoke [31]. Other airway predisposing conditions involving macrophages [8,9], include genetic disorders such as fibrocystic disease and structural abnormalities associated with chronic inflammation and infection.\nChronic infections in which TH1-activated macrophages play a major role, tuberculosis and AIDS, enhance the risk of severe infection, with odds ratios of 1.7 and 2.3– respectively. TH2-dependent asthma may not enhance COVID-19 susceptibility, possibly correlated with low levels of ACE2 expression [44]. IL-13 also reduces ACE2 expression, suggesting that M2-macrophages may contribute to viral resistance. BCG and other immunisations may transiently promote non-specific resistance to SARS-CoV2 [45], to be confirmed in trials. Mononuclear phagocytes are implicated in selected genetic [46] or acquired systemic immunodeficiency, immunosuppression and autoimmunity, including chronic renal disease requiring organ transplantation. Tumor associated macrophages (TAM) and Myeloid derived suppressor cells (MDSC) promote malignancy and metastasis, and with chemo-and radiotherapy may enhance COVID-19 risk. Microglia contribute to neurodegeneration through interaction with neurons in Alzheimer disease, a comorbidity independent of age.\nComorbidities are likely to be multifactorial, and not all display an obvious macrophage link; for example, the ACE2 locus on the X chromosome [47] may contribute to the decreased risk of females [48], but genetic and environmental factors underlying gender, racial and individual disparities remain unclear. Therapeutics for many comorbidities impact on macrophage inflammatory and metabolic functions, including statins, sugar stabilizers, anti-hypertensives and anti-inflammatory agents; control of diabetes and obesity are important in preventing severe infection. Glucocorticoids, which have potent anti-inflammatory effects on macrophages, are contra-indicated in early infection, while protecting against severe disease; timing of administration is therefore critical [49]. The use of anti-TNF antibody in treatment of rheumatoid arthritis, protects against subsequent severe COVID-19 requiring hospitalization [50].\nIn conclusion, the present evidence for a common macrophage contribution to a range of comorbidities is correlative, rather than causal. Nor is it clear whether they increase the risk as well as the severity of infection. Macrophages are central to inflammation, immunity and metabolic diseases, but further genetic and cellular studies are needed to provide a unifying hypothesis.\n\n3.3 Asymptomatic and initial, mild infection\nThere is little direct evidence how monocytes and tissue macrophages contribute to asymptomatic infection, but their tissue distribution, receptor repertoire and secretory capacity are vital to viral resistance as well as dissemination. Acute macrophage antiviral and inflammatory responses determine the outcome of infection, together with other innate and adaptive host mechanisms. We outline evidence from clinical [20] and experimental observations from earlier [51] and current [20] coronavirus studies and consider the role of macrophages and monocytes in local and systemic infections, the antiviral and inflammatory response, resolution and complications.\nMost COVID-19 infections follow droplet inhalation and upper respiratory airway infection, which can be asymptomatic or mild, depending on mucosal immunity and IgA protection. Nasopharyngeal epithelium expresses ACE2 and is an early target for infection. Even if local tissue macrophages do not express ACE2 receptors and are not directly infected, they play a role in inflammatory cytokine responses to infected cells through surface, endosomal and cytosolic receptors and secretion of IL-1 family members [52] and antiviral interferons (IFNs). Monocytes, dendritic cells and tissue macrophages can bind virus through lectin-like receptors such as CD169 [53], for transport to regional lymph nodes. Delivery of virus droplets to the lower respiratory tract leads to infection of ACE2+ alveolar epithelium and capillary endothelium. Detection of intracellular RNA in alveolar macrophages could result from uptake of infected epithelial and endothelial cell debris rather than active infection. Single cell mRNA studies of bronchoalveolar lavage in COVID-19, have confirmed the recruitment of inflammatory monocytes as well as the presence of reactive alveolar macrophages in lung [17,18].\nSeveral common symptoms of early infection can be the indirect result of epithelial cell necrosis by viral infection mediated by ACE2 and/or other co-receptors, such as transmembrane protease serine 2, (TMPRSS2) [13]. Uptake of virus or epithelial cell debris by lung macrophages can initiate inflammasome activation by P2RX7 and release IL-1β, Type1 IFN, IL-6 and TNF [3], contributing to fever, pain, lethargy and headache. Raised levels of C-reactive protein (CRP), induced in hepatocytes by IL-6, are acute phase, plasma biomarkers of COVID-19. Other macrophage products include chemokines such as IL-8 (CXCL8) and MCP-1 (CCL2), recruiting abundant PMN and monocytes to sites of infection. Through viraemia COVID-19 reaches systemic organs such as heart, gut, brain and kidney, which contain resident and recruited macrophage populations; these contribute to local, specialised dysfunctions, such as myocarditis and cardiac arrhythmia, following interactions of macrophages and infected cardiomyocytes [54]. Intravascular coagulation [3,24] promotes dissemination of microthrombi-emboli to lungs, heart and brain, and fibrin degradation d-dimers appear in blood. This is evidence of early resolution, enhanced by the generation of antiviral IgM and IgG.\nWe have little understanding of the innate and adaptive mechanisms that fail to clear local viral infection and at what stage IFN [55,56], other pro-inflammatory [57] and haematopoietic responses become dysregulated in blood monocytes [58]. Together with compromised lung oxygenation, this can lead to systemic immune and vascular dysfunctions. A syndrome of mild infection in younger subjects gives rise to chilblain-like inflammation in toes and fingers [59]. The uncommon multisystem Kawasaki-like inflammatory syndrome of children results from atypical immune responses to COVID-19 [60,61]. This involves anti-viral antibody, systemic vasculitis affecting heart rather than lung, and can respond to corticosteroids. Apart from platelet activation, mononuclear phagocytes are known to produce tissue factor and other procoagulants [62], Factors 5 and 13; fibrinolysis by vascular endothelium and inflammatory macrophages [63] is mediated by secretion of urokinase, which cleaves plasminogen to plasmin; its activity is regulated by inhibitors in plasma, such as alpha2 macroglobulin. Anticoagulants and intranasal or inhaled Type1 IFN may be useful inhibitors of thrombosis and local viral infection, limiting progression to more severe infection.\n\n3.4 Moderate and severe infection: the hyperinflammatory syndrome\nBetween 8–12 days after COVID-19 infection, patients can progress to severe lung infection characterized by pneumonia, increased vascular permeability, edema, and hypoxia, requiring oxygen or mechanical ventilation. This is part of a systemic viral infection of ACE2+epithelia and endothelia, widespread cell death, ischaemia, hypotension and organ failure. Blood analysis at time of hospitalization, has revealed polymorphonuclear leukocytosis, altered levels of abnormal monocytes and lymphopaenia [58,64]. Myeloid cell recruitment to lung contributes to the hyperinflammatory and coagulopathy acute respiratory distress syndrome (ARDS) [20]. This is accompanied by monocyte/macrophage dysregulated production of secretory products. It is not clear which factors contribute to this complication: enhanced viral growth–perhaps triggered by early, poorly neutralizing IgM and complement or IgG, hypoxia and loss of antiviral mechanisms of macrophages–directly or secondary to lymphopaenia, massive local epithelial and endothelial necrosis, hyperactivation of newly recruited immature monocytes, or a “perfect storm” encompassing several of the above. This syndrome could be triggered by induction of ACE2 on specific populations of monocytes and macrophages, resulting in their direct infection. By this stage, spleen and draining nodes at sites of infection are severely disorganized [65]. M1-like monocytes carrying virus through CD169 or other receptors, whether infected or not, can disseminate the virus throughout the body by a Trojan horse mechanism [66]. It is not known whether lymphocytes, not infected, die by apoptosis or necrosis, from products of activated lymphocytes or macrophages such as TNF, or by phagoptosis. We summarize evidence that blood monocytes and activated tissue macrophages contribute to severe COVID-19 and consider virus-induced macrophage pathogenetic mechanisms, which can be targeted therapeutically.\nEarlier studies on SARS1/MERS revealed many of the features of ARDS and of macrophage involvement [6,51]. Initial blood and tissue analysis of COVID-19 provided morphologic evidence of monocyte abnormality and intense macrophage phagocytic activity in infected organs [65]. FACS and single cell RNA analysis of monocytes and broncho-alveolar macrophages [18] provided evidence of emergency myelopoiesis [64] and confirmed the presence of recruited and activated macrophages in alveoli [17] and lung interstitium. Plasma membrane opsonic and other receptors contribute to dysregulated inflammation, monocytic hyperactivation and impaired phagocytic clearance of apoptotic and necrotic cells and debris. Acting through NFkB, RNA, DNA and other sensing and signaling pathways, they initiate production of numerous secretory products. Particular antiviral and proinflammatory products have been targeted for anti-inflammatory treatment, including the IFNs [55,56], IL-1 family [52], IL-6 [27] and TNF [22]. In addition, mononuclear phagocytes interact with plasma cascades, and through upregulated adhesion molecules, with other myeloid and lymphoid cells, platelets, system-wide endothelia and epithelia.\nDysregulated activation of macrophages contributes to the hyperinflammatory and thrombotic pathways of severe COVID-19 [3,24,67].Virus-induced cell injury, apoptosis, necrosis and necroptosis are sensed by distinct, opposing macrophage receptor-dependent effector responses. These include activating and inhibitory pathways of IL-1 production, processing and secretion [52,57], triggered by tissue injury, inflammasome and caspase activation. A highly impaired type1 IFN response, characterized by no IFNβ and low IFNα production and activity, has been associated with persistent viraemia and an exacerbated inflammatory response, partially driven by NFkB, TNF and IL-6 [56]. Endogenous oxidized phospholipids reprogramme macrophage metabolism and boost hyperinflammation [68]. By capturing inflammatory lipids released from dying cells, CD14 induces inflammasome-dependent phagocyte hyperactivation [69]. Macrophage fuel production and utilization [36] are sensitive to hypoxia, HIF-1 responses [70] and iron availability, influencing M1 polarization and effector functions. Activated macrophages trigger coagulation and complement cascades, as well as angiotensin and bradykinin pathways that dysregulate vascular tone and permeability, exacerbating inflammation and edema.\nImmunological processes that may contribute to the outcome of macrophage- viral induced pathology include antibody enhancement of infection (ADE) and inflammation (ADI), and neutrophil NETosis. Anti-spike antiserum can induce hyperinflammation via macrophage FcR, depending on IgG glycosylation and Syk involvement [71]. Cross-reacting antibodies from previous benign coronavirus infections also contribute to enhanced pathology [72]. Dendritic cell dysfunction, ascribed to down regulated HLA-DR expression [67,72] and defective antigen presentation to T and B lymphocytes, may result from lack of costimulatory signals, aborting lymphocyte proliferation and activation and mediating widespread clonal death. Haemophagocytosis, a feature of the macrophage activation syndrome (MAS), is also observed in other viral infections.\n\n3.5 Recovery\nMacrophages are central to the cellular processes which contribute to recovery from COVID-19 infection; they remove debris and necrotic tissue through phagocytosis and secretion of elastase and collagenase, and produce IGF1 and TGF-β to promote tissue recovery. M2-like macrophages are the source of potent lipid metabolites which resolve inflammation; these include resolvins, protectins and maresins, short lived autacoids which regulate the magnitude and duration of acute inflammation [25,73]. Acting through macrophage GPCRs for these metabolites, they enhance efferocytosis of dying neutrophils, and counter inflammation without immunosuppression.\nRecovery can be prolonged after severe infection, involving fever, lethargy, scarring and loss of organ function. Italiani and colleagues profiled the course of resolving versus persistent inflammation with special reference to IL-1 family molecules [57]. An independent single cell mRNA analysis of peripheral blood mononuclear cells during early recovery of COVID-19 infection [23], revealed an increased ratio and level of classical CD14++IL-1β+ monocytes. Further studies are needed to compare monocytes and tissue macrophages after mild or severe infection and to establish whether repolarisation of macrophages from M1 to an M2 phenotype can promote resolution and recovery after COVID-19. After helminth infection, M2 macrophages express resistin, which protects against LPS-induced toxic shock [74]. New or repurposed therapies may be able to modify the sequelae of severe infection."}

{"project":"MyTest","denotations":[{"id":"32861199-32171076-26409812","span":{"begin":238,"end":239},"obj":"32171076"},{"id":"32861199-32444460-26409813","span":{"begin":240,"end":241},"obj":"32444460"},{"id":"32861199-32171076-26409814","span":{"begin":1698,"end":1699},"obj":"32171076"},{"id":"32861199-32444460-26409815","span":{"begin":1700,"end":1701},"obj":"32444460"},{"id":"32861199-32675364-26409816","span":{"begin":1721,"end":1723},"obj":"32675364"},{"id":"32861199-31262653-26409817","span":{"begin":1779,"end":1781},"obj":"31262653"},{"id":"32861199-30046148-26409818","span":{"begin":2048,"end":2050},"obj":"30046148"},{"id":"32861199-32675364-26409819","span":{"begin":2269,"end":2271},"obj":"32675364"},{"id":"32861199-25879284-26409820","span":{"begin":2630,"end":2632},"obj":"25879284"},{"id":"32861199-25612251-26409821","span":{"begin":2633,"end":2635},"obj":"25612251"},{"id":"32861199-30428148-26409822","span":{"begin":2741,"end":2743},"obj":"30428148"},{"id":"32861199-32139904-26409823","span":{"begin":2835,"end":2837},"obj":"32139904"},{"id":"32861199-31130465-26409824","span":{"begin":2912,"end":2914},"obj":"31130465"},{"id":"32861199-32139904-26409825","span":{"begin":2987,"end":2989},"obj":"32139904"},{"id":"32861199-32325025-26409826","span":{"begin":3236,"end":3238},"obj":"32325025"},{"id":"32861199-14748748-26409827","span":{"begin":3299,"end":3301},"obj":"14748748"},{"id":"32861199-28662662-26409828","span":{"begin":3644,"end":3646},"obj":"28662662"},{"id":"32861199-25277499-26409829","span":{"begin":3792,"end":3794},"obj":"25277499"},{"id":"32861199-30936493-26409830","span":{"begin":3878,"end":3880},"obj":"30936493"},{"id":"32861199-30936493-26409831","span":{"begin":4021,"end":4023},"obj":"30936493"},{"id":"32861199-31262653-26409832","span":{"begin":4294,"end":4296},"obj":"31262653"},{"id":"32861199-32171076-26409833","span":{"begin":4359,"end":4360},"obj":"32171076"},{"id":"32861199-32444460-26409834","span":{"begin":4361,"end":4362},"obj":"32444460"},{"id":"32861199-31953710-26409835","span":{"begin":5088,"end":5090},"obj":"31953710"},{"id":"32861199-32471903-26409836","span":{"begin":6455,"end":6457},"obj":"32471903"},{"id":"32861199-32534467-26409837","span":{"begin":7308,"end":7310},"obj":"32534467"},{"id":"32861199-31883097-26409838","span":{"begin":7356,"end":7358},"obj":"31883097"},{"id":"32861199-32534467-26409839","span":{"begin":7373,"end":7375},"obj":"32534467"},{"id":"32861199-32142651-26409840","span":{"begin":8955,"end":8957},"obj":"32142651"},{"id":"32861199-28431249-26409841","span":{"begin":9749,"end":9751},"obj":"28431249"},{"id":"32861199-32651212-26409842","span":{"begin":10131,"end":10133},"obj":"32651212"},{"id":"32861199-32386460-26409843","span":{"begin":10457,"end":10459},"obj":"32386460"},{"id":"32861199-31048328-26409844","span":{"begin":10835,"end":10837},"obj":"31048328"},{"id":"32861199-4427092-26409845","span":{"begin":10925,"end":10927},"obj":"4427092"},{"id":"32861199-32534467-26409846","span":{"begin":11959,"end":11961},"obj":"32534467"},{"id":"32861199-32145185-26409847","span":{"begin":13357,"end":13358},"obj":"32145185"},{"id":"32861199-31883097-26409848","span":{"begin":13359,"end":13361},"obj":"31883097"},{"id":"32861199-32651212-26409849","span":{"begin":14211,"end":14213},"obj":"32651212"},{"id":"32861199-32278362-26409850","span":{"begin":14256,"end":14258},"obj":"32278362"},{"id":"32861199-31768073-26409851","span":{"begin":15233,"end":15235},"obj":"31768073"},{"id":"32861199-29045901-26409852","span":{"begin":15361,"end":15363},"obj":"29045901"},{"id":"32861199-30428148-26409853","span":{"begin":15410,"end":15412},"obj":"30428148"},{"id":"32861199-30275460-26409854","span":{"begin":15457,"end":15459},"obj":"30275460"},{"id":"32861199-29302056-26409855","span":{"begin":17072,"end":17074},"obj":"29302056"},{"id":"32861199-32377375-26409856","span":{"begin":17613,"end":17615},"obj":"32377375"},{"id":"32861199-29133417-26409857","span":{"begin":18036,"end":18038},"obj":"29133417"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"3 COVID-19 infection\n3.1 It is customary to divide the course of the infection into different stages: Preinfection (co-morbidities), asymptomatic, early clinical, severe clinical (acute respiratory distress syndrome–ARDS), and recovery [8,9], Fig. 2 . This natural timing should be used to establish key point-of-care sampling timepoints, avoiding patient discomfort and to focus resources. Infection can progress or be aborted at every stage, presenting a dynamic continuum, to which macrophages and monocytes contribute, together with other immune and non-immune elements; MPS contributions to COVID-19 resistance and pathogenesis are still underestimated and poorly understood.\nFig. 2 Decision points that determine the outcome of COVID-19 infection and requirements for a monocyte activation assay. A time and severity pattern has emerged for COVID-19 progression. The first days, first and second week timelines are turning points for resolution or deterioration. Epidemiologic precision for these milestones and precise parameters will be valuable for strategic sampling and patient stratification, sparing resources and patient material. With limited volumes of peripheral blood, a window on progression of the infection can be obtained by studying activation of the mononuclear phagocyte system, largely represented by monocytes in blood. The cells are biosynthetically active and relatively long lived, ideal to trace long term effects of comorbidities and infection. We highlight selected functional categories that should be addressed in monocytes and can be adapted to particular applications.\n\n3.2 Co-morbidities and the mps\nMacrophage activities contribute to many co- morbidities [8,9], including aging [28], obesity [29], diabetes [30], exposure to pollutants [31], and microbiome properties [32]. Macrophage functions alter with age, together with adaptive immune processes such as thymic involution, which deplete T lymphocyte reserves. Chronic, low grade inflammation (INFLAMMAGING) has been proposed as a predisposing factor [33]. This may result from failure of macrophages and NK cells to clear increasing accumulation of senescent cells, that enhance basal levels of inflammation and interfere with subsequent adaptive immunity upon infection [28]. Baseline inflammation may not be detrimental in itself, but can initiate an inflammatory cascade that amplifies excessive inflammation occurring in response to pathogens. Age-related metabolic correlates of macrophage dysfunction include innate lymphoid cell interactions with adipose tissue and associated macrophages, as well as inflammasome activation [34,35]. This affects thermogenesis, part of a wider metabolic syndrome involving glucose and lipid metabolism [36], elevated body mass index (BMI), type 1 and type 2 diabetes, obesity and atherosclerosis [37]. These correlate with macrophage metabolic and mitochondrial activities [38] and, possibly, ACE2 expression and hypertension, another co-morbidity [37]. ACE2, the COVID-19 entry receptor, is widely expressed on microvascular endothelium and binds the SARS-CoV2 spike glycoprotein implicated in angiotensin regulation by its competition with ACE1, and potential role as an anti-inflammatory agent [39]. Macrophages in tuberculosis and sarcoidosis express ACE1 [40], but expression of ACE2 by monocytes and tissue macrophages has not been validated [41]; evidence for productive infection of macrophages via ACE2 is incomplete [15]. Macrophages express scavenger receptors including Axl and MERTK, tyrosine kinase receptors implicated in phosphatidyl serine recognition and phagocytosis of apoptotic cells [21]; Axl is a coreceptor for ACE2+ dependent infection of other cell types by COVID-19 and other enveloped viruses via surface or endocytic routes [42], the basis for a clinical trial involving an Axl inhibitor.\nAlveolar macrophages [43] are close to Type 1 pneumocytes, involved in gas exchange, Type 2 surfactant-producing pneumocytes, and capillary endothelium, all ACE 2+ [43]. They take up and store atmospheric pollutants and poorly-degradable pro-inflammatory particles; host DNA from dying cells can induce the innate STING pathway after uptake and also activate inflammasomes in lung macrophages after exposure to ozone and cigarette smoke [31]. Other airway predisposing conditions involving macrophages [8,9], include genetic disorders such as fibrocystic disease and structural abnormalities associated with chronic inflammation and infection.\nChronic infections in which TH1-activated macrophages play a major role, tuberculosis and AIDS, enhance the risk of severe infection, with odds ratios of 1.7 and 2.3– respectively. TH2-dependent asthma may not enhance COVID-19 susceptibility, possibly correlated with low levels of ACE2 expression [44]. IL-13 also reduces ACE2 expression, suggesting that M2-macrophages may contribute to viral resistance. BCG and other immunisations may transiently promote non-specific resistance to SARS-CoV2 [45], to be confirmed in trials. Mononuclear phagocytes are implicated in selected genetic [46] or acquired systemic immunodeficiency, immunosuppression and autoimmunity, including chronic renal disease requiring organ transplantation. Tumor associated macrophages (TAM) and Myeloid derived suppressor cells (MDSC) promote malignancy and metastasis, and with chemo-and radiotherapy may enhance COVID-19 risk. Microglia contribute to neurodegeneration through interaction with neurons in Alzheimer disease, a comorbidity independent of age.\nComorbidities are likely to be multifactorial, and not all display an obvious macrophage link; for example, the ACE2 locus on the X chromosome [47] may contribute to the decreased risk of females [48], but genetic and environmental factors underlying gender, racial and individual disparities remain unclear. Therapeutics for many comorbidities impact on macrophage inflammatory and metabolic functions, including statins, sugar stabilizers, anti-hypertensives and anti-inflammatory agents; control of diabetes and obesity are important in preventing severe infection. Glucocorticoids, which have potent anti-inflammatory effects on macrophages, are contra-indicated in early infection, while protecting against severe disease; timing of administration is therefore critical [49]. The use of anti-TNF antibody in treatment of rheumatoid arthritis, protects against subsequent severe COVID-19 requiring hospitalization [50].\nIn conclusion, the present evidence for a common macrophage contribution to a range of comorbidities is correlative, rather than causal. Nor is it clear whether they increase the risk as well as the severity of infection. Macrophages are central to inflammation, immunity and metabolic diseases, but further genetic and cellular studies are needed to provide a unifying hypothesis.\n\n3.3 Asymptomatic and initial, mild infection\nThere is little direct evidence how monocytes and tissue macrophages contribute to asymptomatic infection, but their tissue distribution, receptor repertoire and secretory capacity are vital to viral resistance as well as dissemination. Acute macrophage antiviral and inflammatory responses determine the outcome of infection, together with other innate and adaptive host mechanisms. We outline evidence from clinical [20] and experimental observations from earlier [51] and current [20] coronavirus studies and consider the role of macrophages and monocytes in local and systemic infections, the antiviral and inflammatory response, resolution and complications.\nMost COVID-19 infections follow droplet inhalation and upper respiratory airway infection, which can be asymptomatic or mild, depending on mucosal immunity and IgA protection. Nasopharyngeal epithelium expresses ACE2 and is an early target for infection. Even if local tissue macrophages do not express ACE2 receptors and are not directly infected, they play a role in inflammatory cytokine responses to infected cells through surface, endosomal and cytosolic receptors and secretion of IL-1 family members [52] and antiviral interferons (IFNs). Monocytes, dendritic cells and tissue macrophages can bind virus through lectin-like receptors such as CD169 [53], for transport to regional lymph nodes. Delivery of virus droplets to the lower respiratory tract leads to infection of ACE2+ alveolar epithelium and capillary endothelium. Detection of intracellular RNA in alveolar macrophages could result from uptake of infected epithelial and endothelial cell debris rather than active infection. Single cell mRNA studies of bronchoalveolar lavage in COVID-19, have confirmed the recruitment of inflammatory monocytes as well as the presence of reactive alveolar macrophages in lung [17,18].\nSeveral common symptoms of early infection can be the indirect result of epithelial cell necrosis by viral infection mediated by ACE2 and/or other co-receptors, such as transmembrane protease serine 2, (TMPRSS2) [13]. Uptake of virus or epithelial cell debris by lung macrophages can initiate inflammasome activation by P2RX7 and release IL-1β, Type1 IFN, IL-6 and TNF [3], contributing to fever, pain, lethargy and headache. Raised levels of C-reactive protein (CRP), induced in hepatocytes by IL-6, are acute phase, plasma biomarkers of COVID-19. Other macrophage products include chemokines such as IL-8 (CXCL8) and MCP-1 (CCL2), recruiting abundant PMN and monocytes to sites of infection. Through viraemia COVID-19 reaches systemic organs such as heart, gut, brain and kidney, which contain resident and recruited macrophage populations; these contribute to local, specialised dysfunctions, such as myocarditis and cardiac arrhythmia, following interactions of macrophages and infected cardiomyocytes [54]. Intravascular coagulation [3,24] promotes dissemination of microthrombi-emboli to lungs, heart and brain, and fibrin degradation d-dimers appear in blood. This is evidence of early resolution, enhanced by the generation of antiviral IgM and IgG.\nWe have little understanding of the innate and adaptive mechanisms that fail to clear local viral infection and at what stage IFN [55,56], other pro-inflammatory [57] and haematopoietic responses become dysregulated in blood monocytes [58]. Together with compromised lung oxygenation, this can lead to systemic immune and vascular dysfunctions. A syndrome of mild infection in younger subjects gives rise to chilblain-like inflammation in toes and fingers [59]. The uncommon multisystem Kawasaki-like inflammatory syndrome of children results from atypical immune responses to COVID-19 [60,61]. This involves anti-viral antibody, systemic vasculitis affecting heart rather than lung, and can respond to corticosteroids. Apart from platelet activation, mononuclear phagocytes are known to produce tissue factor and other procoagulants [62], Factors 5 and 13; fibrinolysis by vascular endothelium and inflammatory macrophages [63] is mediated by secretion of urokinase, which cleaves plasminogen to plasmin; its activity is regulated by inhibitors in plasma, such as alpha2 macroglobulin. Anticoagulants and intranasal or inhaled Type1 IFN may be useful inhibitors of thrombosis and local viral infection, limiting progression to more severe infection.\n\n3.4 Moderate and severe infection: the hyperinflammatory syndrome\nBetween 8–12 days after COVID-19 infection, patients can progress to severe lung infection characterized by pneumonia, increased vascular permeability, edema, and hypoxia, requiring oxygen or mechanical ventilation. This is part of a systemic viral infection of ACE2+epithelia and endothelia, widespread cell death, ischaemia, hypotension and organ failure. Blood analysis at time of hospitalization, has revealed polymorphonuclear leukocytosis, altered levels of abnormal monocytes and lymphopaenia [58,64]. Myeloid cell recruitment to lung contributes to the hyperinflammatory and coagulopathy acute respiratory distress syndrome (ARDS) [20]. This is accompanied by monocyte/macrophage dysregulated production of secretory products. It is not clear which factors contribute to this complication: enhanced viral growth–perhaps triggered by early, poorly neutralizing IgM and complement or IgG, hypoxia and loss of antiviral mechanisms of macrophages–directly or secondary to lymphopaenia, massive local epithelial and endothelial necrosis, hyperactivation of newly recruited immature monocytes, or a “perfect storm” encompassing several of the above. This syndrome could be triggered by induction of ACE2 on specific populations of monocytes and macrophages, resulting in their direct infection. By this stage, spleen and draining nodes at sites of infection are severely disorganized [65]. M1-like monocytes carrying virus through CD169 or other receptors, whether infected or not, can disseminate the virus throughout the body by a Trojan horse mechanism [66]. It is not known whether lymphocytes, not infected, die by apoptosis or necrosis, from products of activated lymphocytes or macrophages such as TNF, or by phagoptosis. We summarize evidence that blood monocytes and activated tissue macrophages contribute to severe COVID-19 and consider virus-induced macrophage pathogenetic mechanisms, which can be targeted therapeutically.\nEarlier studies on SARS1/MERS revealed many of the features of ARDS and of macrophage involvement [6,51]. Initial blood and tissue analysis of COVID-19 provided morphologic evidence of monocyte abnormality and intense macrophage phagocytic activity in infected organs [65]. FACS and single cell RNA analysis of monocytes and broncho-alveolar macrophages [18] provided evidence of emergency myelopoiesis [64] and confirmed the presence of recruited and activated macrophages in alveoli [17] and lung interstitium. Plasma membrane opsonic and other receptors contribute to dysregulated inflammation, monocytic hyperactivation and impaired phagocytic clearance of apoptotic and necrotic cells and debris. Acting through NFkB, RNA, DNA and other sensing and signaling pathways, they initiate production of numerous secretory products. Particular antiviral and proinflammatory products have been targeted for anti-inflammatory treatment, including the IFNs [55,56], IL-1 family [52], IL-6 [27] and TNF [22]. In addition, mononuclear phagocytes interact with plasma cascades, and through upregulated adhesion molecules, with other myeloid and lymphoid cells, platelets, system-wide endothelia and epithelia.\nDysregulated activation of macrophages contributes to the hyperinflammatory and thrombotic pathways of severe COVID-19 [3,24,67].Virus-induced cell injury, apoptosis, necrosis and necroptosis are sensed by distinct, opposing macrophage receptor-dependent effector responses. These include activating and inhibitory pathways of IL-1 production, processing and secretion [52,57], triggered by tissue injury, inflammasome and caspase activation. A highly impaired type1 IFN response, characterized by no IFNβ and low IFNα production and activity, has been associated with persistent viraemia and an exacerbated inflammatory response, partially driven by NFkB, TNF and IL-6 [56]. Endogenous oxidized phospholipids reprogramme macrophage metabolism and boost hyperinflammation [68]. By capturing inflammatory lipids released from dying cells, CD14 induces inflammasome-dependent phagocyte hyperactivation [69]. Macrophage fuel production and utilization [36] are sensitive to hypoxia, HIF-1 responses [70] and iron availability, influencing M1 polarization and effector functions. Activated macrophages trigger coagulation and complement cascades, as well as angiotensin and bradykinin pathways that dysregulate vascular tone and permeability, exacerbating inflammation and edema.\nImmunological processes that may contribute to the outcome of macrophage- viral induced pathology include antibody enhancement of infection (ADE) and inflammation (ADI), and neutrophil NETosis. Anti-spike antiserum can induce hyperinflammation via macrophage FcR, depending on IgG glycosylation and Syk involvement [71]. Cross-reacting antibodies from previous benign coronavirus infections also contribute to enhanced pathology [72]. Dendritic cell dysfunction, ascribed to down regulated HLA-DR expression [67,72] and defective antigen presentation to T and B lymphocytes, may result from lack of costimulatory signals, aborting lymphocyte proliferation and activation and mediating widespread clonal death. Haemophagocytosis, a feature of the macrophage activation syndrome (MAS), is also observed in other viral infections.\n\n3.5 Recovery\nMacrophages are central to the cellular processes which contribute to recovery from COVID-19 infection; they remove debris and necrotic tissue through phagocytosis and secretion of elastase and collagenase, and produce IGF1 and TGF-β to promote tissue recovery. M2-like macrophages are the source of potent lipid metabolites which resolve inflammation; these include resolvins, protectins and maresins, short lived autacoids which regulate the magnitude and duration of acute inflammation [25,73]. Acting through macrophage GPCRs for these metabolites, they enhance efferocytosis of dying neutrophils, and counter inflammation without immunosuppression.\nRecovery can be prolonged after severe infection, involving fever, lethargy, scarring and loss of organ function. Italiani and colleagues profiled the course of resolving versus persistent inflammation with special reference to IL-1 family molecules [57]. An independent single cell mRNA analysis of peripheral blood mononuclear cells during early recovery of COVID-19 infection [23], revealed an increased ratio and level of classical CD14++IL-1β+ monocytes. Further studies are needed to compare monocytes and tissue macrophages after mild or severe infection and to establish whether repolarisation of macrophages from M1 to an M2 phenotype can promote resolution and recovery after COVID-19. After helminth infection, M2 macrophages express resistin, which protects against LPS-induced toxic shock [74]. New or repurposed therapies may be able to modify the sequelae of severe infection."}