Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition.
Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition.
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DOI：
10.1182/blood.2020008248
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发表时间：
2020-10-29
期刊：
影响因子：
20.3
通讯作者：
Brodsky RA
中科院分区：
文献类型：
--
作者：
Yu J;Yuan X;Chen H;Chaturvedi S;Braunstein EM;Brodsky RA
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是一种高度传染性的呼吸道病毒，可导致静脉/动脉血栓形成、中风、肾衰竭、心肌梗死、血小板减少症和其他终末器官损害。在C3缺陷小鼠中证明终末器官保护的动物模型和人类补体激活的证据导致了SARS-CoV-2触发补体介导的内皮损伤的假设，但机制尚不清楚。在这里，我们证明了SARS-CoV-2刺突蛋白（亚基1和2），而不是N蛋白，直接激活补体旁路途径（APC）。使用改良Ham试验的补体依赖性杀伤被C5或因子D抑制阻断。C3片段和C5 b-9沉积在TF 1 PIGAnull靶细胞上，并且补体因子Bb在来自刺突蛋白处理的细胞的上清液中增加。C5抑制可阻止C5 b-9在细胞上的蓄积，但不能阻止C3 c;然而，因子D抑制可阻止C3 c和C5 b-9蓄积。因子H的添加减轻了补体攻击。总之，SARS-CoV-2刺突蛋白通过阻止细胞表面APC转化酶的失活将非活化剂表面转化为活化剂表面。APC激活可以解释COVID-19的许多临床表现（微血管病、血小板减少症、肾损伤和血栓形成倾向），这些临床表现也在其他补体驱动的疾病中观察到，如非典型溶血性尿毒综合征和灾难性抗磷脂抗体综合征。C5抑制可防止C5 b-9在体外积聚，但不能防止上游补体激活对SARS-CoV-2刺突蛋白的应答。SARS-CoV-2刺突蛋白结合硫酸乙酰肝素并激活细胞表面的补体旁路途径。D因子抑制剂（ACH 145951）阻断SARS-CoV-2刺突蛋白诱导的补体激活。
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. SARS-CoV-2 spike proteins bind heparan sulfate and activate the alternative complement pathway on cell surfaces. Factor D inhibitor (ACH145951) blocks the complement activation induced by SARS-CoV-2 spike proteins.
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影响因子：
20.3
作者：
Harder, Markus J.;Kuhn, Nadine;Schmidt, Christoph Q.
通讯作者：
Schmidt, Christoph Q.
影响因子：
20.3
作者：
Chaturvedi, Shruti;Braunstein, Evan M.;Brodsky, Robert A.
通讯作者：
Brodsky, Robert A.
影响因子：
20.3
作者：
Hillmen, Peter;Muus, Petra;Young, Neal S.
通讯作者：
Young, Neal S.
DOI：
10.1146/annurev-genom-090413-025610
发表时间：
2014
影响因子：
8.7
作者：
Fritsche LG;Fariss RN;Stambolian D;Abecasis GR;Curcio CA;Swaroop A
通讯作者：
Swaroop A
影响因子：
10.1
作者：
Brodsky RA;Peffault de Latour R;Rottinghaus ST;Röth A;Risitano AM;Weitz IC;Hillmen P;Maciejewski JP;Szer J;Lee JW;Kulasekararaj AG;Volles L;Damokosh AI;Ortiz S;Shafner L;Liu P;Hill A;Schrezenmeier H
通讯作者：
Schrezenmeier H