Triggering Innate Immunity
Despite immune evasion and subverting innate immune responses during early infection SARS-CoV-2 effectively initiates immune signalling pathways. This is likely due to the increased viral load that exponentially produces viral RNA and viral proteins (pathogen associated molecular patterns – PAMPS), also induces cell damage that release damage associated molecular patterns (DAMPS) both of which trigger innate immune pathways.
Like SARS-CoV and NL63, SARS-CoV-2 uses the angiotensin (Ang)-converting enzyme-2 (ACE2) as a cell receptor [Table 1] expressed on epithelia in renal, cardiovascular and gastrointestinal tract tissues, testes and on pneumocytes and vascular endothelia (66), and is increased in diabetes possibly explaining the increased susceptibility in this population. ACE2 regulates the renin-angiotensin system (RAS) by balancing the conversion of angiotensin I to angiotensin 1–9 and angiotensin II to angiotensin 1–7. Binding of SARS-CoV-2 to ACE2 leads to endosome formation reducing ACE2 expression on the cell surface (51) [figures 3 and 4] pushes the RAS system to a pro-inflammatory mode triggering production of reactive oxygen species, fibrosis, collagen deposition and a proinflammatory environment including IL-6 and IL-8 production by macrophages and recruitment of neutrophils [figure 4]. Thus, binding and entry of SARS-CoV-2 via the ACE2 is likely to be the first step in a line of augmented and detrimental immune responses in COVID-19, that involves complement activation, innate immune activation via PAMPS and DAMPS, inflammasome activation and pyroptosis, NK cell activation, hyperactivation of macrophages, neutrophils and innate T cells and induction of a cytokine storm as discussed below.