Lectin Pathway Mediates Complement Activation by SARS-CoV-2 Proteins.
Lectin Pathway Mediates Complement Activation by SARS-CoV-2 Proteins.
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DOI：
10.3389/fimmu.2021.714511
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发表时间：
2021
影响因子：
7.3
通讯作者：
Schwaeble WJ
中科院分区：
文献类型：
--
作者：
Ali YM;Ferrari M;Lynch NJ;Yaseen S;Dudler T;Gragerov S;Demopulos G;Heeney JL;Schwaeble WJ
补体的早期和持续激活被认为在COVID-19的发病机制中起关键作用。补体激活产物通过将细胞免疫系统的细胞募集到感染部位并将其激活状态转变为炎症表型，协调促炎环境，这可能对诱导和维持对SARS-CoV-2的严重炎症反应至关重要。它先于病理生理里程碑事件，如细胞因子风暴、进行性内皮损伤引发微血管病变和进一步的补体激活，并导致急性呼吸窘迫综合征（ARDS）。迄今为止，抗病毒药物和皮质类固醇的应用在SARS-CoV-2感染的早期阶段显示出疗效，但未能改善进展为严重COVID-19病理的患者的疾病严重程度。本报告表明，补体系统的凝集素途径（LP）识别分子，如MBL、FCN-2和CL-11，与SARS-CoV-2的S-和n -蛋白结合，随后激活LP介导的C3b和C4b沉积。此外，我们的研究结果证实并强调了SARS-CoV-2的n蛋白直接与LP效应酶MASP-2结合并激活补体。使用针对MASP-2的抑制性单克隆抗体抑制LP可有效阻断LP介导的补体激活。利用转染的表达sars - cov - 2s蛋白的HEK-293细胞进行的FACS分析证实，在细胞表面存在强大的lp依赖性C3b沉积，该沉积被MASP-2抑制抗体抑制。鉴于我们目前的结果，以及我们的临床候选MASP-2抑制剂Narsoplimab在最近发表的临床试验中的令人鼓舞的表现，我们认为靶向MASP-2为治疗重症COVID-19提供了无与伦比的治疗效果窗口。
Early and persistent activation of complement is considered to play a key role in the pathogenesis of COVID-19. Complement activation products orchestrate a proinflammatory environment that might be critical for the induction and maintenance of a severe inflammatory response to SARS-CoV-2 by recruiting cells of the cellular immune system to the sites of infection and shifting their state of activation towards an inflammatory phenotype. It precedes pathophysiological milestone events like the cytokine storm, progressive endothelial injury triggering microangiopathy, and further complement activation, and causes an acute respiratory distress syndrome (ARDS). To date, the application of antiviral drugs and corticosteroids have shown efficacy in the early stages of SARS-CoV-2 infection, but failed to ameliorate disease severity in patients who progressed to severe COVID-19 pathology. This report demonstrates that lectin pathway (LP) recognition molecules of the complement system, such as MBL, FCN-2 and CL-11, bind to SARS-CoV-2 S- and N-proteins, with subsequent activation of LP-mediated C3b and C4b deposition. In addition, our results confirm and underline that the N-protein of SARS-CoV-2 binds directly to the LP- effector enzyme MASP-2 and activates complement. Inhibition of the LP using an inhibitory monoclonal antibody against MASP-2 effectively blocks LP-mediated complement activation. FACS analyses using transfected HEK-293 cells expressing SARS-CoV-2 S protein confirm a robust LP-dependent C3b deposition on the cell surface which is inhibited by the MASP-2 inhibitory antibody. In light of our present results, and the encouraging performance of our clinical candidate MASP-2 inhibitor Narsoplimab in recently published clinical trials, we suggest that the targeting of MASP-2 provides an unsurpassed window of therapeutic efficacy for the treatment of severe COVID-19.
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
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影响因子：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Schwaeble, Wilhelm J.
DOI：
10.1016/j.dsx.2020.04.020
发表时间：
2020-07-01
影响因子：
10
作者：
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通讯作者：
Ysrafil