3.3  Asymptomatic and initial, mild infection
There 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.
Most 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].
Several 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.
We 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.