Complement
SARS-CoV-2 is heavily decorated with glycans [figure 1] that
recognised by DC-SIGN and other lectins that facilitate viral uptake by
dendritic cells. Glycans also activate the lectin complement pathway
following binding of mannose binding protein (MBP) to SARS-CoV-2 viral
proteins expressed on infected cells [figures 1 and 2]. Pathology
studies and transcriptional profiles of tissues from COVID-19 cases
reveal robust activation of the complement system with deposition of
MBL, C4d, C3 and C5b-9 forming the membrane attack complex (MAC), in
alveolar and epithelial cells (67,68) [figure 4]. In addition, C4d
and C5b-9 deposits in lung and skin microvasculature co-localised with
spike glycoproteins indicates systemic complement activation supporting
the role of complement in tissue damage (67). Importantly, activation of
the lectin, as well as the classical pathway following antibody binding
to viral proteins, likely contributes to cell damage [figure 4,
(69)] by either direct complement mediated lysis or via antibody
dependent cell mediated cytotoxicity. Of relevance to the coagulation
dysfunction, thrombosis and vascular damage observed following
SARS-CoV-2 infection is that complement components induce secretion of
von Willebrand factor (70) but also promotes monocyte and neutrophil
recruitment as well as stimulates NET formation (71) that in turn
perpetuates complement activation [figure 4]. Complement may thus
contribute to widespread tissue damage in SARS-CoV2 infected cases. The
pathogenic role of complement in disease is supported by findings in
mice. For example, mice deficient in C3 had similar viral load as
wildtype mice but lacked the overt pathology with fewer neutrophils and
macrophages in the lung (72). Thus, while complement activation is not
required for control of virus infection it likely plays a key role in
the tissue damage.