Hyperinflammation and severe COVID-19
The delayed interferon response, increased viral load and virus dissemination, coupled with the release of DAMPS and PAMPs lead to activation of several innate immune pathways. Following infection, pneumocytes, epithelial and alveolar cells, and infiltrating monocyte-macrophages and neutrophils likely produce the first wave of TNFα, IL-6, IP-10, MCP-1, MIP-1α and RANTES production (86,87). Hyperinflammation is likely promoted by comorbidities due to increased ACE2 expression, concurrent bacterial infections, ageing as well as a direct effect of SARS-CoV-2 replication since virus-host interactome studies reveal that SARS-CoV-2 nsp10 regulates the NFκB repressor factor NKRF, facilitating IL-8 production (88). This is followed by a second wave of cell recruitment including NK cells that produce IFNγ and further recruitment of (alternatively activated) monocytes/macrophages and neutrophils [figure 4] as observed in bronchial lavages, post-mortem tissues and peripheral blood studies (87). NK cells are key players in disease outcome of infection critically balancing the direct response to the virus by eliminating infected cells while also augmenting tissue damage [figure 4]. Likely aided by IFNγ induction by NK cells hyperinflammation in severe COVID-19 is also characterised by recruitment of immature and mature human monocyte-derived DCs that harbour SARS-CoV infection, however, infection is abortive and mature virions are not released. During infection DCs express only low levels of cytokines likely due to innate immune subversion strategies. The sustained activation of infiltrating monocytes and monocyte-derived macrophages (89) observed in severe COVID-19 cases is likely driven by a number of factors including oxidative stress, anti-SARS-CoV-2 antibody:antigen complexes, NLRP3 inflammasome activation, and complement activation that converge to sustain an aberrant hyperinflammatory response, or cytokine storm (90). Following SARS-CoV-2 infection one of the first innate immune cells to infiltrate into the tissues are neutrophils likely recruited by CXCL2 and CXCL8 generated by infected cells (91). While neutrophils do not clear viral particles, they phagocytose apoptotic bodies containing virus and debris releasing proteolytic enzymes, antimicrobial peptides, matrix metalloproteinases and high levels of ROS to inactivate viruses. A key function of neutrophils relevant to the pathology of SARS-CoV2 is the production of neutrophil extracellular traps (NETs) generated in response to endothelial damage, ROS production, IL-1β production and virus replication [figure 4, reviewed in (92)]. The formation of NETs by neutrophils are aided by activated platelets associated with damaged endothelial cells that further activate the complement fuelling the coagulation cascade and thrombi formation. While the NETs act to prevent further spread of the virus they trigger platelet activation and bind erythrocytes thereby promoting (micro)thrombi formation [figure 4].