Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC). Complement-dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGAnull target cells, and complement factor Bb is increased in the supernatant from spike protein-treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert nonactivator surfaces to activator surfaces by preventing the inactivation of the cell-surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.
【초록키워드】 COVID-19, SARS-CoV-2, coronavirus, thrombosis, antibody, stroke, Human, complement, endothelial damage, in vitro, Spike protein, cells, respiratory virus, mice, inactivation, animal, SARS-CoV-2 spike protein, Myocardial infarction, disease, mechanism, Alternative pathway, Evidence, Hypothesis, Injury, Atypical, Trigger, target cells, clinical manifestation, acute respiratory syndrome, Activation, subunit, syndrome, SARS-CoV-2 spike proteins, renal, contagious, supernatant, upstream, killing, end-organ damage, uremic syndrome, mitigate, Prevent, catastrophic, blocked, activate, explain, the N protein, APC, C3c, end-organ, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2 spike protein, Complement pathway, Activation, Direct, blocked,