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].