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.