Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry.
Coagulation factors directly cleave SARS-CoV-2 spike and enhance viral entry.
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DOI：
10.7554/elife.77444
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发表时间：
2022-03-23
期刊：
影响因子：
7.7
通讯作者：
Cantley L
中科院分区：
文献类型：
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作者：
Kastenhuber ER;Mercadante M;Nilsson-Payant B;Johnson JL;Jaimes JA;Muecksch F;Weisblum Y;Bram Y;Chandar V;Whittaker GR;tenOever BR;Schwartz RE;Cantley L
凝血障碍是 COVID-19 患者发病的一个重要方面。凝血级联由一系列蛋白酶传播，包括 Xa 因子和凝血酶。虽然已知某些宿主蛋白酶（包括 TMPRSS2 和弗林蛋白酶）对于 SARS-CoV-2 刺突的裂解激活非常重要，从而促进病毒进入呼吸道，但其他蛋白酶也可能有所贡献。通过生化和基于细胞的检测，我们证明 Xa 因子和凝血酶也可以直接裂解 SARS-CoV-2 刺突，从而增强病毒进入阶段的感染。凝血因子增加了人肺类器官中 SARS-CoV-2 的感染。药物再利用筛选确定了蛋白酶抑制剂的一个子集，它们混杂地抑制跨膜丝氨酸蛋白酶和凝血因子的尖峰切割。蛋白酶抑制剂 nafamostat 和 camostat 的机制可能超出了抑制 TMPRSS2 的范围，延伸至凝血诱导的尖峰裂解。抗凝治疗对于 COVID-19 的治疗至关重要，早期干预可以通过抑制 SARS-CoV-2 病毒进入来提供附带益处。我们提出了一种正反馈模型，感染引起的高凝会加剧 SARS-CoV-2 的感染性。
Coagulopathy is a significant aspect of morbidity in COVID-19 patients. The clotting cascade is propagated by a series of proteases, including factor Xa and thrombin. While certain host proteases, including TMPRSS2 and furin, are known to be important for cleavage activation of SARS-CoV-2 spike to promote viral entry in the respiratory tract, other proteases may also contribute. Using biochemical and cell-based assays, we demonstrate that factor Xa and thrombin can also directly cleave SARS-CoV-2 spike, enhancing infection at the stage of viral entry. Coagulation factors increased SARS-CoV-2 infection in human lung organoids. A drug-repurposing screen identified a subset of protease inhibitors that promiscuously inhibited spike cleavage by both transmembrane serine proteases and coagulation factors. The mechanism of the protease inhibitors nafamostat and camostat may extend beyond inhibition of TMPRSS2 to coagulation-induced spike cleavage. Anticoagulation is critical in the management of COVID-19, and early intervention could provide collateral benefit by suppressing SARS-CoV-2 viral entry. We propose a model of positive feedback whereby infection-induced hypercoagulation exacerbates SARS-CoV-2 infectivity.