Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within the family Coronaviridae. It is an enveloped single-stranded positive-sense RNA virus. Since December of 2019, a global expansion of the infection has occurred with widespread dissemination of coronavirus disease 2019 (COVID-19). COVID-19 often manifests as only mild cold-like symptomatology, but severe disease with complications occurs in 15% of cases. Respiratory failure occurs in severe disease that can be accompanied by a systemic inflammatory reaction characterized by inflammatory cytokine release. In severe cases, fatality is caused by the rapid development of severe lung injury characteristic of acute respiratory distress syndrome (ARDS). Although ARDS is a complication of SARS-CoV-2 infection, it is not viral replication or infection that causes tissue injury; rather, it is the result of dysregulated hyperinflammation in response to viral infection. This pathology is characterized by intense, rapid stimulation of the innate immune response that triggers activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway and release of its products including the proinflammatory cytokines IL-6 and IL-1β. Here we review the literature that describes the pathogenesis of severe COVID-19 and NLRP3 activation and describe an important role in targeting this pathway for the treatment of severe COVID-19.
Highlights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within the family Coronaviridae
Severe cases result in acute respiratory distress syndrome (ARDS) with systemic inflammation in which lung injury is associated with release of inflammatory cytokines IL-6 and IL-1β [2, 4]
Individuals infected with SARS-CoV-2 can present with an array of clinical severity from asymptomatic through severe disease characterized by pneumonia requiring supplemental oxygen, and progression to acute respiratory distress syndrome (ARDS) with systemic inflammatory response syndrome (SIRS), shock and multiorgan dysfunction, coagulopathy, and death [27]
Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within the family Coronaviridae. SARS-CoV 3a protein activates the NLRP3 inflammasome in lipopolysaccharide-primed macrophages with 3a-mediated IL-1β secretion associated with K+ efflux and mitochondrial reactive oxygen species [15]. Individuals infected with SARS-CoV-2 can present with an array of clinical severity from asymptomatic through severe disease characterized by pneumonia requiring supplemental oxygen, and progression to acute respiratory distress syndrome (ARDS) with systemic inflammatory response syndrome (SIRS), shock and multiorgan dysfunction, coagulopathy, and death [27]. Individuals with COVID19 who experience more mild disease have lower levels of IL-6, together with activated T lymphocytes and IgM SARS-CoV-2binding antibodies [41] These observations indicate that a robust inflammatory cytokine response mediates severe disease while low inflammatory cytokine responses may be associated with an adaptive response that favors disease resolution. Programmed cell death through multiple mechanisms has been reported in coronavirus infections as an important mechanism of viral pathogenesis [83,84,85,86,87,88]
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