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of SPMs and Their Receptors in Virus Infections\nBecause viruses are obligate intracellular parasites, viruses must enter target cells and multiply using host cell machinery to produce progeny viruses (Ryu 2017). The various stages involved in viral growth that occur inside cells are called the viral life cycle. The viral life cycle can be divided into three stages: entry, genome replication, and exit. Entry can be subdivided into attachment, penetration and uncoating, and exit can be subdivided into virion assembly and release. Genome replication differs by virus type. Many studies are showing that SPMs regulate the inflammatory response caused by viral infections, but studies on the effects of SPMs on the viral life cycle have been difficult to find. There have a few reports recently. For example, among SPMs, LXA4 modulates Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) life cycle through chromatin modulation and hedgehog signalling to destabilize the latency of herpes virus and decreases the expression of programmed death-ligand 1 (PD-L1) in Kaposi’s Sarcoma, thereby reducing immune evasion (Fig. 3) (Asha et al. 2020). On the other hand, there are not a few reports that the receptors mentioned above for SPMs act as receptors in virus infection (see below). So, in this section, we will discuss the effect of SPMs on the virus and the viral infection-induced inflammation and mention how the receptors of SPMs affect the life cycle of the virus (Fig. 3).\n\nInfluenza\nInfluenza viruses are a well-studied model for understanding the role of inflammation resolution mediators and the mechanism of viral infection. This is because different viruses elicit different host immune responses and outcomes. From studies comparing more virulent influenza virus strains to less virulent strains, it has been reported that pro-resolving mediators have an inverse correlation with the biological activity of the virus (Cilloniz et al. 2010). The more toxic strains of influenza induced reduction of LXs, which increased the spread of the virus. LXB4 recently improved IgG production in B cells from donors vaccinated against influenza virus, suggesting potential as a novel adjuvant. (Kim et al. 2018).\nAnnexin is the most abundant host cell protein in the virion, and annexin A1 (ANXA1) contributes to influenza-induced toxicity (Tcherniuk et al. 2016). That is, during virus entry into the host cell, viral hemagglutinin (HA) not only binds sialic acid but also ANXA1 binds to FPR2, resulting in activation of ERK2 and increased viral replication (Tcherniuk et al. 2016). RvD1 and LXA4 also activate FPR2. It is still unknown whether RvD1 and LXA4 compete with viral annexin at the receptors site leads to the prevention of viral infection or the promotion of viral replication. However, it is reported that AT-RvD1 reduces inflammation caused by the viral infection. (Wang et al. 2017). Increased SAA in recurrent acute exacerbations of COPD caused by bacterial and virus coinfection acts as a functional agonist of FPR2/ALX, antagonizing the protective action of FPR2/ALX by AT-RvD1, promoting chemotaxis of neutrophils and prolonging survival (Wang et al. 2018).\nThere are no reports of direct research on whether RvD1, the same family as AT-RvD1, inhibits the influenza virus. However, it promotes inflammation and removal of bacteria caused by a bacterial infection. For example, RvD1 relieves lung inflammation and promotes the elimination of untypeable Haemophilus influenza (Croasdell et al. 2016). ChemR23, a receptor for RvE1, relieves lung inflammation and enhances antiviral immunity in a mouse model of acute viral pneumonia (Bondue et al., 2011). Therefore, it would be fascinating to study whether RvE1 is effective in pneumonia caused by the influenza virus.\nPD1 has pivotal and multiple roles in regulating viral pathogenicity. Influenza strains, such as the lethal H5N1, down-regulate PD1 (Tam et al. 2013). There is an inverse correlation between the level of PD1 and the level of pathogenicity of various virus isolates. In addition to the host’s inflammatory response, PD1 has a direct antiviral action against influenza. Both PD1 and its isomer PDX (LOX-mediated double oxygenation) limit viral replication by interfering with the viral RNA nuclear transport mechanism (Fig. 3) (Imai 2015; Morita et al. 2013; Baillie and Digard 2013). Treatment of infected mice with PD1 improves survival, even if administered 48 hours after the onset of infection when the current antiviral therapy is no longer significantly effective (Fig. 4) (Morita et al. 2013; Ng et al. 2010).\n\nHerpes simplex virus\nHerpesviruses 1 and 2 (HSV-1 and HSV-2), with the taxonomic names human alphaherpesvirus 1 and human alphaherpesvirus 2, are the most common causes of human viral infections among the members of the human Herpesviridae family (Chayavichitsilp et al. 2009). Herpes simplex virus (HSV) ocular infection represents another example in which local control of the virus stems from a robust inflammatory response with long-term consequences of chronic inflammation, including the possibility of final blindness due to interstitial keratitis that persists even after the viral infection has been cleared.\nIn animals with HSV, topical administration of RvE1 reduced the influx of CD4+ T cells (both TH1 cells and TH17 cells) and neutrophils, decreased production of inflammatory cytokines including IFNγ and IL-6, and increased levels of the anti-inflammatory cytokine IL-10 (Fig. 4) (Rajasagi et al. 2011). Overall, RvE1 significantly reduced stromal keratitis. Similar results were demonstrated with PD1 (Fig. 4) (Rajasagi et al. 2013). Besides, AT-RvD1 treatment significantly reduced the degree of corneal angiogenesis and the severity of stromal keratitis lesions, and AT-RvD1 treated mice had fewer Th1 and Th17 cells in the infected cornea, as well as the reduced number of inflammatory cells, including neutrophils (Rajasagi et al. 2017).\n\nRespiratory syncytial virus, human immunodeficiency virus, and hepatitis C virus\nRespiratory syncytial virus (RSV), also known as human respiratory cell fusion virus (HRSV) and human orthopneumovirus, is a virus that causes respiratory infections in which infected mucosal cells fuse to form a syncytium (Schweitzer and Justice 2020). It is the leading cause of lower respiratory tract infections and hospital visits in infancy and childhood (Read and Bosco 2020). RSV infection results in bronchiolitis, which is classically caused by activated macrophages and eventually resolved by alternatively activated macrophages (Shirey et al. 2010). The promotion of these two alternative macrophage fates appears to be related to RSV-induced COX-2 and LXA4 and RvE1-mediated protective measures (Fig. 4) (Richardson et al. 2005; Shirey et al. 2014). Also, although it does not directly act on the virus, RvD1 inhibits inflammatory signal transduction by polyinosinic-polycytidylic acid, an analogue of RNAs derived from respiratory viruses such as RSV, and the action of RvD1 is mediated by FPR2/ALX and GPR32 (Hsiao et al. 2014). These reports suggest the critical role of SPMs and lipid mediator class shift in the host’s response to RSV in the initial control and final infection clearance.\nHuman immunodeficiency virus (HIV) is a lentivirus (a subgroup of retroviruses) and are classified into two based on the genetic characteristics and viral antigen, HIV-1 and HIV-2. HIV infection may progress to acquired immunodeficiency syndrome (AIDS), a progressive failure of the immune system. Over time, AIDS causes life-threatening opportunistic infections and a condition in which cancer thrives (Douek et al. 2009; Powell et al. 2016).\nWhen co-cultured with HIV-1 infected mononuclear cells and human glial cells (astrocytoma, glial and primary human astrocyte), tumour necrosis factor alpha (TNF-α) and interleukin-1β are produced, and large amounts of LTB4, LTD4, LXA4, and PAF, were also found in media from this co-culture (Fig. 4) (Genis et al. 1992). So far, this is the only in vitro study to prove, that LXs are produced in direct response to viral infection. However, the role of LXs in this infection model has not been investigated. Synthetic peptides derived from human immunodeficiency virus type 1 gp120 activate the 7-transmembrane GPCR FPR2/ALX, down-regulating the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes (Deng et al. 1999).\nFPR2/ALX acts as an efficient core receptor for the primary isolate of HIV (Shimizu et al. 2008). Viral entries through the alternative core receptors (CoR) CCR3 and FPR2/ALX depend on the HIV type 1 subtype. Viruses pseudotyped with subtype A and C Env proteins use the recently described alternative CoR FPR2 more efficiently than CCR3 (Nedellec et al. 2009). ChemR23 also acts as a CoR for HIV. At this time, HIV-1 and HIV-2 appear to use the N-terminus and the second extracellular loop of ChemR23 during infection (Martensson et al. 2006). As mentioned above, research is needed to determine the role of SPMs that act as ligands for FPR2 and ChemR23 in HIV infection.\nHepatitis C virus (HCV) is a positive-sense single-stranded RNA virus of the family Flaviviridae with a small (55–65 nm size) envelope (Lee et al. 2017). The HCV is the cause of hepatitis C and some cancers such as liver cancer (hepatocellular carcinoma, abbreviated HCC) and lymphoma in humans (Ferri et al. 2015; Rusyn and Lemon 2014). To date, there appears to be no report on the effectiveness of SPMs against HCV. However, HCV peptide (C5A), an amphiphilic α-helix peptide of HCV, is an activator of the N-formyl peptide receptor in human phagocytes (Lin et al. 2011). This suggests the possibility of interaction between RvD1 and LXA4, FPR families, and HCV. Vitamin D metabolites inhibit HCV and upregulate GPR37 gene expression, which induces cellular autophagy (Gutierrez et al. 2014). PD1 was recently proposed as a new ligand for GPR37, and some studies suggest a possible relationship between PD1 and HCV (Fig. 4). SAA also has antiviral effects against HCV, however, it induces chronic inflammation through FPR2/ALX, causing liver damage (Abouelasrar Salama et al. 2019). Although research has not been conducted yet, RvD1 and LXA4, which inhibit the action of SAA, are likely to suppress liver damage caused by SAA during HCV infection.\n\nSARS-CoV-2\nSevere acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) refers to a coronavirus strain that causes 2019 coronavirus disease (COVID-19), a respiratory disease that is the cause of the COVID-19 pandemic (Coronaviridae Study Group of the International Committee on Taxonomy of, 2020). SARS-CoV-2 is an RNA virus that infects the lungs and causes deaths through complications such as cytokine storms (Goldin et al. 2020).\nThe anti-inflammatory action of mesenchymal stem cells is well known, and it is believed that these mesenchymal stem cells exhibit anti-inflammatory action through PGE2 and LXA4. These lipids mediators alleviate the SARS-CoV-2 cytokine storm, while arachidonic acid, dihomo-gamma-linolenic acid, and gamma-linolenic acid inactivate enveloped viruses (Das 2020). Obesity is a risk factor for SARS-CoV-2 infection, and a BMI of 30 kg/m2 increases the risk of infection by 61% (Bello-Chavolla et al. 2020). This is likely due to a deficiency of SPMs in obese patients, and this deficiency promotes adverse reactions during SARS-CoV-2 infection (Pal et al. 2020). LXA4, Elovanoid-N32 or RvD6 isomers reduced expression of angiotensin-converting enzyme 2 (ACE2), but NDP1 did not reduce it. These lipids mediators also counteract the binding of the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein to the injured cornea (Figs. 3 and 4) (Pham et al. 2020). Elovanoid-N32 or RvD6 isomers also attenuated the expression of cytokines involved in a cytokine storm and hyperinflammation. Based on previous study results that have demonstrated SPMs as potential therapeutic targets for SARS-CoV-2 infection, studies and review on the use of fish oil, an SPMs precursor, as an adjuvant are in progress. (Torrinhas et al. 2020; Rogero et al. 2020). SPMs and soluble epoxide hydrolase inhibitors are currently in clinical trials for other inflammatory diseases and can be quickly converted and used for SARS-CoV-2 management through the removal of cellular debris and inhibition of inflammatory cytokines (Panigrahy et al. 2020)."}

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The various stages involved in viral growth that occur inside cells are called the viral life cycle. The viral life cycle can be divided into three stages: entry, genome replication, and exit. Entry can be subdivided into attachment, penetration and uncoating, and exit can be subdivided into virion assembly and release. Genome replication differs by virus type. Many studies are showing that SPMs regulate the inflammatory response caused by viral infections, but studies on the effects of SPMs on the viral life cycle have been difficult to find. There have a few reports recently. For example, among SPMs, LXA4 modulates Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) life cycle through chromatin modulation and hedgehog signalling to destabilize the latency of herpes virus and decreases the expression of programmed death-ligand 1 (PD-L1) in Kaposi’s Sarcoma, thereby reducing immune evasion (Fig. 3) (Asha et al. 2020). On the other hand, there are not a few reports that the receptors mentioned above for SPMs act as receptors in virus infection (see below). So, in this section, we will discuss the effect of SPMs on the virus and the viral infection-induced inflammation and mention how the receptors of SPMs affect the life cycle of the virus (Fig. 3).\n\nInfluenza\nInfluenza viruses are a well-studied model for understanding the role of inflammation resolution mediators and the mechanism of viral infection. This is because different viruses elicit different host immune responses and outcomes. From studies comparing more virulent influenza virus strains to less virulent strains, it has been reported that pro-resolving mediators have an inverse correlation with the biological activity of the virus (Cilloniz et al. 2010). The more toxic strains of influenza induced reduction of LXs, which increased the spread of the virus. LXB4 recently improved IgG production in B cells from donors vaccinated against influenza virus, suggesting potential as a novel adjuvant. (Kim et al. 2018).\nAnnexin is the most abundant host cell protein in the virion, and annexin A1 (ANXA1) contributes to influenza-induced toxicity (Tcherniuk et al. 2016). That is, during virus entry into the host cell, viral hemagglutinin (HA) not only binds sialic acid but also ANXA1 binds to FPR2, resulting in activation of ERK2 and increased viral replication (Tcherniuk et al. 2016). RvD1 and LXA4 also activate FPR2. It is still unknown whether RvD1 and LXA4 compete with viral annexin at the receptors site leads to the prevention of viral infection or the promotion of viral replication. However, it is reported that AT-RvD1 reduces inflammation caused by the viral infection. (Wang et al. 2017). Increased SAA in recurrent acute exacerbations of COPD caused by bacterial and virus coinfection acts as a functional agonist of FPR2/ALX, antagonizing the protective action of FPR2/ALX by AT-RvD1, promoting chemotaxis of neutrophils and prolonging survival (Wang et al. 2018).\nThere are no reports of direct research on whether RvD1, the same family as AT-RvD1, inhibits the influenza virus. However, it promotes inflammation and removal of bacteria caused by a bacterial infection. For example, RvD1 relieves lung inflammation and promotes the elimination of untypeable Haemophilus influenza (Croasdell et al. 2016). ChemR23, a receptor for RvE1, relieves lung inflammation and enhances antiviral immunity in a mouse model of acute viral pneumonia (Bondue et al., 2011). Therefore, it would be fascinating to study whether RvE1 is effective in pneumonia caused by the influenza virus.\nPD1 has pivotal and multiple roles in regulating viral pathogenicity. Influenza strains, such as the lethal H5N1, down-regulate PD1 (Tam et al. 2013). There is an inverse correlation between the level of PD1 and the level of pathogenicity of various virus isolates. In addition to the host’s inflammatory response, PD1 has a direct antiviral action against influenza. Both PD1 and its isomer PDX (LOX-mediated double oxygenation) limit viral replication by interfering with the viral RNA nuclear transport mechanism (Fig. 3) (Imai 2015; Morita et al. 2013; Baillie and Digard 2013). Treatment of infected mice with PD1 improves survival, even if administered 48 hours after the onset of infection when the current antiviral therapy is no longer significantly effective (Fig. 4) (Morita et al. 2013; Ng et al. 2010).\n\nHerpes simplex virus\nHerpesviruses 1 and 2 (HSV-1 and HSV-2), with the taxonomic names human alphaherpesvirus 1 and human alphaherpesvirus 2, are the most common causes of human viral infections among the members of the human Herpesviridae family (Chayavichitsilp et al. 2009). Herpes simplex virus (HSV) ocular infection represents another example in which local control of the virus stems from a robust inflammatory response with long-term consequences of chronic inflammation, including the possibility of final blindness due to interstitial keratitis that persists even after the viral infection has been cleared.\nIn animals with HSV, topical administration of RvE1 reduced the influx of CD4+ T cells (both TH1 cells and TH17 cells) and neutrophils, decreased production of inflammatory cytokines including IFNγ and IL-6, and increased levels of the anti-inflammatory cytokine IL-10 (Fig. 4) (Rajasagi et al. 2011). Overall, RvE1 significantly reduced stromal keratitis. Similar results were demonstrated with PD1 (Fig. 4) (Rajasagi et al. 2013). Besides, AT-RvD1 treatment significantly reduced the degree of corneal angiogenesis and the severity of stromal keratitis lesions, and AT-RvD1 treated mice had fewer Th1 and Th17 cells in the infected cornea, as well as the reduced number of inflammatory cells, including neutrophils (Rajasagi et al. 2017).\n\nRespiratory syncytial virus, human immunodeficiency virus, and hepatitis C virus\nRespiratory syncytial virus (RSV), also known as human respiratory cell fusion virus (HRSV) and human orthopneumovirus, is a virus that causes respiratory infections in which infected mucosal cells fuse to form a syncytium (Schweitzer and Justice 2020). It is the leading cause of lower respiratory tract infections and hospital visits in infancy and childhood (Read and Bosco 2020). RSV infection results in bronchiolitis, which is classically caused by activated macrophages and eventually resolved by alternatively activated macrophages (Shirey et al. 2010). The promotion of these two alternative macrophage fates appears to be related to RSV-induced COX-2 and LXA4 and RvE1-mediated protective measures (Fig. 4) (Richardson et al. 2005; Shirey et al. 2014). Also, although it does not directly act on the virus, RvD1 inhibits inflammatory signal transduction by polyinosinic-polycytidylic acid, an analogue of RNAs derived from respiratory viruses such as RSV, and the action of RvD1 is mediated by FPR2/ALX and GPR32 (Hsiao et al. 2014). These reports suggest the critical role of SPMs and lipid mediator class shift in the host’s response to RSV in the initial control and final infection clearance.\nHuman immunodeficiency virus (HIV) is a lentivirus (a subgroup of retroviruses) and are classified into two based on the genetic characteristics and viral antigen, HIV-1 and HIV-2. HIV infection may progress to acquired immunodeficiency syndrome (AIDS), a progressive failure of the immune system. Over time, AIDS causes life-threatening opportunistic infections and a condition in which cancer thrives (Douek et al. 2009; Powell et al. 2016).\nWhen co-cultured with HIV-1 infected mononuclear cells and human glial cells (astrocytoma, glial and primary human astrocyte), tumour necrosis factor alpha (TNF-α) and interleukin-1β are produced, and large amounts of LTB4, LTD4, LXA4, and PAF, were also found in media from this co-culture (Fig. 4) (Genis et al. 1992). So far, this is the only in vitro study to prove, that LXs are produced in direct response to viral infection. However, the role of LXs in this infection model has not been investigated. Synthetic peptides derived from human immunodeficiency virus type 1 gp120 activate the 7-transmembrane GPCR FPR2/ALX, down-regulating the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes (Deng et al. 1999).\nFPR2/ALX acts as an efficient core receptor for the primary isolate of HIV (Shimizu et al. 2008). Viral entries through the alternative core receptors (CoR) CCR3 and FPR2/ALX depend on the HIV type 1 subtype. Viruses pseudotyped with subtype A and C Env proteins use the recently described alternative CoR FPR2 more efficiently than CCR3 (Nedellec et al. 2009). ChemR23 also acts as a CoR for HIV. At this time, HIV-1 and HIV-2 appear to use the N-terminus and the second extracellular loop of ChemR23 during infection (Martensson et al. 2006). As mentioned above, research is needed to determine the role of SPMs that act as ligands for FPR2 and ChemR23 in HIV infection.\nHepatitis C virus (HCV) is a positive-sense single-stranded RNA virus of the family Flaviviridae with a small (55–65 nm size) envelope (Lee et al. 2017). The HCV is the cause of hepatitis C and some cancers such as liver cancer (hepatocellular carcinoma, abbreviated HCC) and lymphoma in humans (Ferri et al. 2015; Rusyn and Lemon 2014). To date, there appears to be no report on the effectiveness of SPMs against HCV. However, HCV peptide (C5A), an amphiphilic α-helix peptide of HCV, is an activator of the N-formyl peptide receptor in human phagocytes (Lin et al. 2011). This suggests the possibility of interaction between RvD1 and LXA4, FPR families, and HCV. Vitamin D metabolites inhibit HCV and upregulate GPR37 gene expression, which induces cellular autophagy (Gutierrez et al. 2014). PD1 was recently proposed as a new ligand for GPR37, and some studies suggest a possible relationship between PD1 and HCV (Fig. 4). SAA also has antiviral effects against HCV, however, it induces chronic inflammation through FPR2/ALX, causing liver damage (Abouelasrar Salama et al. 2019). Although research has not been conducted yet, RvD1 and LXA4, which inhibit the action of SAA, are likely to suppress liver damage caused by SAA during HCV infection.\n\nSARS-CoV-2\nSevere acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) refers to a coronavirus strain that causes 2019 coronavirus disease (COVID-19), a respiratory disease that is the cause of the COVID-19 pandemic (Coronaviridae Study Group of the International Committee on Taxonomy of, 2020). SARS-CoV-2 is an RNA virus that infects the lungs and causes deaths through complications such as cytokine storms (Goldin et al. 2020).\nThe anti-inflammatory action of mesenchymal stem cells is well known, and it is believed that these mesenchymal stem cells exhibit anti-inflammatory action through PGE2 and LXA4. These lipids mediators alleviate the SARS-CoV-2 cytokine storm, while arachidonic acid, dihomo-gamma-linolenic acid, and gamma-linolenic acid inactivate enveloped viruses (Das 2020). Obesity is a risk factor for SARS-CoV-2 infection, and a BMI of 30 kg/m2 increases the risk of infection by 61% (Bello-Chavolla et al. 2020). This is likely due to a deficiency of SPMs in obese patients, and this deficiency promotes adverse reactions during SARS-CoV-2 infection (Pal et al. 2020). LXA4, Elovanoid-N32 or RvD6 isomers reduced expression of angiotensin-converting enzyme 2 (ACE2), but NDP1 did not reduce it. These lipids mediators also counteract the binding of the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein to the injured cornea (Figs. 3 and 4) (Pham et al. 2020). Elovanoid-N32 or RvD6 isomers also attenuated the expression of cytokines involved in a cytokine storm and hyperinflammation. Based on previous study results that have demonstrated SPMs as potential therapeutic targets for SARS-CoV-2 infection, studies and review on the use of fish oil, an SPMs precursor, as an adjuvant are in progress. (Torrinhas et al. 2020; Rogero et al. 2020). SPMs and soluble epoxide hydrolase inhibitors are currently in clinical trials for other inflammatory diseases and can be quickly converted and used for SARS-CoV-2 management through the removal of cellular debris and inhibition of inflammatory cytokines (Panigrahy et al. 2020)."}

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of SPMs and Their Receptors in Virus Infections\nBecause viruses are obligate intracellular parasites, viruses must enter target cells and multiply using host cell machinery to produce progeny viruses (Ryu 2017). The various stages involved in viral growth that occur inside cells are called the viral life cycle. The viral life cycle can be divided into three stages: entry, genome replication, and exit. Entry can be subdivided into attachment, penetration and uncoating, and exit can be subdivided into virion assembly and release. Genome replication differs by virus type. Many studies are showing that SPMs regulate the inflammatory response caused by viral infections, but studies on the effects of SPMs on the viral life cycle have been difficult to find. There have a few reports recently. For example, among SPMs, LXA4 modulates Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) life cycle through chromatin modulation and hedgehog signalling to destabilize the latency of herpes virus and decreases the expression of programmed death-ligand 1 (PD-L1) in Kaposi’s Sarcoma, thereby reducing immune evasion (Fig. 3) (Asha et al. 2020). On the other hand, there are not a few reports that the receptors mentioned above for SPMs act as receptors in virus infection (see below). So, in this section, we will discuss the effect of SPMs on the virus and the viral infection-induced inflammation and mention how the receptors of SPMs affect the life cycle of the virus (Fig. 3).\n\nInfluenza\nInfluenza viruses are a well-studied model for understanding the role of inflammation resolution mediators and the mechanism of viral infection. This is because different viruses elicit different host immune responses and outcomes. From studies comparing more virulent influenza virus strains to less virulent strains, it has been reported that pro-resolving mediators have an inverse correlation with the biological activity of the virus (Cilloniz et al. 2010). The more toxic strains of influenza induced reduction of LXs, which increased the spread of the virus. LXB4 recently improved IgG production in B cells from donors vaccinated against influenza virus, suggesting potential as a novel adjuvant. (Kim et al. 2018).\nAnnexin is the most abundant host cell protein in the virion, and annexin A1 (ANXA1) contributes to influenza-induced toxicity (Tcherniuk et al. 2016). That is, during virus entry into the host cell, viral hemagglutinin (HA) not only binds sialic acid but also ANXA1 binds to FPR2, resulting in activation of ERK2 and increased viral replication (Tcherniuk et al. 2016). RvD1 and LXA4 also activate FPR2. It is still unknown whether RvD1 and LXA4 compete with viral annexin at the receptors site leads to the prevention of viral infection or the promotion of viral replication. However, it is reported that AT-RvD1 reduces inflammation caused by the viral infection. (Wang et al. 2017). Increased SAA in recurrent acute exacerbations of COPD caused by bacterial and virus coinfection acts as a functional agonist of FPR2/ALX, antagonizing the protective action of FPR2/ALX by AT-RvD1, promoting chemotaxis of neutrophils and prolonging survival (Wang et al. 2018).\nThere are no reports of direct research on whether RvD1, the same family as AT-RvD1, inhibits the influenza virus. However, it promotes inflammation and removal of bacteria caused by a bacterial infection. For example, RvD1 relieves lung inflammation and promotes the elimination of untypeable Haemophilus influenza (Croasdell et al. 2016). ChemR23, a receptor for RvE1, relieves lung inflammation and enhances antiviral immunity in a mouse model of acute viral pneumonia (Bondue et al., 2011). Therefore, it would be fascinating to study whether RvE1 is effective in pneumonia caused by the influenza virus.\nPD1 has pivotal and multiple roles in regulating viral pathogenicity. Influenza strains, such as the lethal H5N1, down-regulate PD1 (Tam et al. 2013). There is an inverse correlation between the level of PD1 and the level of pathogenicity of various virus isolates. In addition to the host’s inflammatory response, PD1 has a direct antiviral action against influenza. Both PD1 and its isomer PDX (LOX-mediated double oxygenation) limit viral replication by interfering with the viral RNA nuclear transport mechanism (Fig. 3) (Imai 2015; Morita et al. 2013; Baillie and Digard 2013). Treatment of infected mice with PD1 improves survival, even if administered 48 hours after the onset of infection when the current antiviral therapy is no longer significantly effective (Fig. 4) (Morita et al. 2013; Ng et al. 2010).\n\nHerpes simplex virus\nHerpesviruses 1 and 2 (HSV-1 and HSV-2), with the taxonomic names human alphaherpesvirus 1 and human alphaherpesvirus 2, are the most common causes of human viral infections among the members of the human Herpesviridae family (Chayavichitsilp et al. 2009). Herpes simplex virus (HSV) ocular infection represents another example in which local control of the virus stems from a robust inflammatory response with long-term consequences of chronic inflammation, including the possibility of final blindness due to interstitial keratitis that persists even after the viral infection has been cleared.\nIn animals with HSV, topical administration of RvE1 reduced the influx of CD4+ T cells (both TH1 cells and TH17 cells) and neutrophils, decreased production of inflammatory cytokines including IFNγ and IL-6, and increased levels of the anti-inflammatory cytokine IL-10 (Fig. 4) (Rajasagi et al. 2011). Overall, RvE1 significantly reduced stromal keratitis. Similar results were demonstrated with PD1 (Fig. 4) (Rajasagi et al. 2013). Besides, AT-RvD1 treatment significantly reduced the degree of corneal angiogenesis and the severity of stromal keratitis lesions, and AT-RvD1 treated mice had fewer Th1 and Th17 cells in the infected cornea, as well as the reduced number of inflammatory cells, including neutrophils (Rajasagi et al. 2017).\n\nRespiratory syncytial virus, human immunodeficiency virus, and hepatitis C virus\nRespiratory syncytial virus (RSV), also known as human respiratory cell fusion virus (HRSV) and human orthopneumovirus, is a virus that causes respiratory infections in which infected mucosal cells fuse to form a syncytium (Schweitzer and Justice 2020). It is the leading cause of lower respiratory tract infections and hospital visits in infancy and childhood (Read and Bosco 2020). RSV infection results in bronchiolitis, which is classically caused by activated macrophages and eventually resolved by alternatively activated macrophages (Shirey et al. 2010). The promotion of these two alternative macrophage fates appears to be related to RSV-induced COX-2 and LXA4 and RvE1-mediated protective measures (Fig. 4) (Richardson et al. 2005; Shirey et al. 2014). Also, although it does not directly act on the virus, RvD1 inhibits inflammatory signal transduction by polyinosinic-polycytidylic acid, an analogue of RNAs derived from respiratory viruses such as RSV, and the action of RvD1 is mediated by FPR2/ALX and GPR32 (Hsiao et al. 2014). These reports suggest the critical role of SPMs and lipid mediator class shift in the host’s response to RSV in the initial control and final infection clearance.\nHuman immunodeficiency virus (HIV) is a lentivirus (a subgroup of retroviruses) and are classified into two based on the genetic characteristics and viral antigen, HIV-1 and HIV-2. HIV infection may progress to acquired immunodeficiency syndrome (AIDS), a progressive failure of the immune system. Over time, AIDS causes life-threatening opportunistic infections and a condition in which cancer thrives (Douek et al. 2009; Powell et al. 2016).\nWhen co-cultured with HIV-1 infected mononuclear cells and human glial cells (astrocytoma, glial and primary human astrocyte), tumour necrosis factor alpha (TNF-α) and interleukin-1β are produced, and large amounts of LTB4, LTD4, LXA4, and PAF, were also found in media from this co-culture (Fig. 4) (Genis et al. 1992). So far, this is the only in vitro study to prove, that LXs are produced in direct response to viral infection. However, the role of LXs in this infection model has not been investigated. Synthetic peptides derived from human immunodeficiency virus type 1 gp120 activate the 7-transmembrane GPCR FPR2/ALX, down-regulating the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes (Deng et al. 1999).\nFPR2/ALX acts as an efficient core receptor for the primary isolate of HIV (Shimizu et al. 2008). Viral entries through the alternative core receptors (CoR) CCR3 and FPR2/ALX depend on the HIV type 1 subtype. Viruses pseudotyped with subtype A and C Env proteins use the recently described alternative CoR FPR2 more efficiently than CCR3 (Nedellec et al. 2009). ChemR23 also acts as a CoR for HIV. At this time, HIV-1 and HIV-2 appear to use the N-terminus and the second extracellular loop of ChemR23 during infection (Martensson et al. 2006). As mentioned above, research is needed to determine the role of SPMs that act as ligands for FPR2 and ChemR23 in HIV infection.\nHepatitis C virus (HCV) is a positive-sense single-stranded RNA virus of the family Flaviviridae with a small (55–65 nm size) envelope (Lee et al. 2017). The HCV is the cause of hepatitis C and some cancers such as liver cancer (hepatocellular carcinoma, abbreviated HCC) and lymphoma in humans (Ferri et al. 2015; Rusyn and Lemon 2014). To date, there appears to be no report on the effectiveness of SPMs against HCV. However, HCV peptide (C5A), an amphiphilic α-helix peptide of HCV, is an activator of the N-formyl peptide receptor in human phagocytes (Lin et al. 2011). This suggests the possibility of interaction between RvD1 and LXA4, FPR families, and HCV. Vitamin D metabolites inhibit HCV and upregulate GPR37 gene expression, which induces cellular autophagy (Gutierrez et al. 2014). PD1 was recently proposed as a new ligand for GPR37, and some studies suggest a possible relationship between PD1 and HCV (Fig. 4). SAA also has antiviral effects against HCV, however, it induces chronic inflammation through FPR2/ALX, causing liver damage (Abouelasrar Salama et al. 2019). Although research has not been conducted yet, RvD1 and LXA4, which inhibit the action of SAA, are likely to suppress liver damage caused by SAA during HCV infection.\n\nSARS-CoV-2\nSevere acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) refers to a coronavirus strain that causes 2019 coronavirus disease (COVID-19), a respiratory disease that is the cause of the COVID-19 pandemic (Coronaviridae Study Group of the International Committee on Taxonomy of, 2020). SARS-CoV-2 is an RNA virus that infects the lungs and causes deaths through complications such as cytokine storms (Goldin et al. 2020).\nThe anti-inflammatory action of mesenchymal stem cells is well known, and it is believed that these mesenchymal stem cells exhibit anti-inflammatory action through PGE2 and LXA4. These lipids mediators alleviate the SARS-CoV-2 cytokine storm, while arachidonic acid, dihomo-gamma-linolenic acid, and gamma-linolenic acid inactivate enveloped viruses (Das 2020). Obesity is a risk factor for SARS-CoV-2 infection, and a BMI of 30 kg/m2 increases the risk of infection by 61% (Bello-Chavolla et al. 2020). This is likely due to a deficiency of SPMs in obese patients, and this deficiency promotes adverse reactions during SARS-CoV-2 infection (Pal et al. 2020). LXA4, Elovanoid-N32 or RvD6 isomers reduced expression of angiotensin-converting enzyme 2 (ACE2), but NDP1 did not reduce it. These lipids mediators also counteract the binding of the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein to the injured cornea (Figs. 3 and 4) (Pham et al. 2020). Elovanoid-N32 or RvD6 isomers also attenuated the expression of cytokines involved in a cytokine storm and hyperinflammation. Based on previous study results that have demonstrated SPMs as potential therapeutic targets for SARS-CoV-2 infection, studies and review on the use of fish oil, an SPMs precursor, as an adjuvant are in progress. (Torrinhas et al. 2020; Rogero et al. 2020). SPMs and soluble epoxide hydrolase inhibitors are currently in clinical trials for other inflammatory diseases and can be quickly converted and used for SARS-CoV-2 management through the removal of cellular debris and inhibition of inflammatory cytokines (Panigrahy et al. 2020)."}