Figure legends
Figure 1. SARS-CoV-2 driven complement activation and potential targets of the complement cascade. Several structural proteins of SARS-CoV-2 including the S and N proteins are recognized by MBL resulting in virus-induced activation of the LP. Sensing of the virus by the innate immune system results in the activation of B and T cells of the adaptive immune system, eventually leading to the production of virus-specific IgM and IgG antibodies. Such antibodies activate the complement system by the CP in addition to the LP. LP and CP activation initiate a cascade or proteolytic events that forms the C4bC2 convertase, eventually cleaving C3 into C3a and C3b. This C3b serves as the nucleus of the amplification (A) loop that results in the ongoing cleavage of C3, unless controlled by complement regulator proteins. The emerging C3 convertase of the AP, C3bBb can form the C5 convertase C3bBb3b of the AP that consecutively cleaves C5a into C5a and C5b, the latter of which can assemble together with C6-C9 to build the MAC. Several compounds have been generated that specifically target the activation of the LP at the level of the serine protease MASP-2 or the CP at the level of C1q and C1s. Further, compounds have been developed to inhibit the cleavage of C3 by either targeting molecules that build the AP C3 convertase of by protecting C3 from C3 convertase-mediated cleavage. Downstream of C3, antibodies and inhibitors of C5 have been generated that protect C5 from cleavage by C5 convertases. Finally, distinct approaches resulted in antibodies that target C5a or antagonists of its primary receptor, C5aR1. The potential use of such complement inhibitors in COVID-19 infection is discussed in the text.
Figure 2. Complement effector functions leading to SARS-CoV-2-induced thrombotic microangiopathy (TMA) and acute lung injury. SARS-CoV-2-sensing by pattern recognition molecules of the LP and CP results in C5 cleavage and the generation of the C5a anaphylatoxin. Further, LP-derived MAPSs activate the coagulation and the kinin system to ignite TMA leading to fibrin formation and platelet aggregation. C5a attracts neutrophils and inflammatory monocytes to adhere at the vascular endothelium, release IL-8 and multiple inflammatory cytokines and form NETs. Such NETs can activate complement by the AP and fuel the C3 amplification loop (A), when complement regulators are exhausted and/or exhibit reduced function due to loss of function mutations. Also, adherent neutrophils produce LTB4 that binds to it cognate receptor driving neutrophil transmigration into the lung. C5a-activated monocytes in concert with activated neutrophils produce proinflammatory cytokines and chemokines that further activate the endothelium and amplify inflammation. Virus-induced complement activation by the LP within the lung tissue is an additional source of C5a. It activates neutrophils and inflammatory monocytes that were recruited to the lung, as well as tissue-resident macrophages to produce pro-inflammatory chemokines and cytokines, eventually driving tissue damage leading to ALI and ARDS development.
Figure 3. Impact of inherited gain- or loss-of function mutations in complement activator or regulator proteins on complement pathway activation. The degree of complement activation in response to infection is defined by the strength of the activation by complement activator molecules, the formation of the critical AP amplification loop and the potency of the system to balance this activation by complement regulator molecules. (A) Balanced complement activation occurs, when sensing of the SARS-CoV-2 virus by MBL or virus-specific antibodies is appropriately controlled by complement regulator proteins resulting in innate immunity-guided activation of adaptive immune responses eventually leading to virus elimination. (B) Polymorphisms in a set of complement proteins, either associated with a gain-of function in complement activators or loss-of function in complement regulators, or both, can aggregate to effects leading to complement overactivation as has been observed in African Americans with HSCT-TMA. In case of SARS-CoV-2 infection, such aggregation of inherited variants of complement proteins may lead to humoral and cellular hyperinflammation, associated with virus persistence and strong immunopathology causing TMA and ARDS.