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.