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.