Complement dysregulation is associated with severe COVID-19 illness.
Complement dysregulation is associated with severe COVID-19 illness.
复制标题
DOI：
10.3324/haematol.2021.279155
复制
发表时间：
2022-05-01
期刊：
影响因子：
10.1
通讯作者：
Brodsky, Robert A.
中科院分区：
文献类型：
--
作者：
Yu, Jia;Gerber, Gloria F.;Chen, Hang;Yuan, Xuan;Chaturvedi, Shruti;Braunstein, Evan M.;Brodsky, Robert A.
严重急性呼吸综合征冠状病毒-2（SARS-CoV-2）可表现为血栓形成、中风、肾衰竭、心肌梗死和血小板减少症，使人联想到其他补体介导的疾病。多项临床和临床前研究表明，补体参与了COVID-19疾病的发病机制。我们先前发现SARS-CoV-2刺突蛋白通过干扰补体因子H（APC的关键负调节因子）的功能在体外激活补体旁路途径（APC）。在这里，我们证明了来自58名COVID-19患者的血清（32名患者具有最低氧气需求，7名患者接受高流量氧气，17名患者需要机械通气，2名患者死亡）可以在功能测定（改良的Ham试验）中诱导补体介导的细胞死亡，并增加细胞表面上的膜攻击复合物（C5 b-9）沉积。在41.2%需要插管的COVID-19患者（n=7/17）中存在阳性改良Ham测定（>20%细胞杀伤），而在需要最低限度氧气支持的COVID-19患者中仅为6.3%（n=2/32）。C5和D因子抑制有效地减轻了COVID-19患者血清诱导的补体扩增。血清因子Bb水平升高与COVID-19患者的疾病严重程度相关，表明APC失调起着重要作用。此外，SARS-CoV-2刺突蛋白直接阻断补体因子H与肝素的结合，这可能导致细胞表面的补体失调。综上所述，我们的数据表明，补体失调有助于COVID-19的发病机制，并可能是疾病严重程度的标志。
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may manifest as thrombosis, stroke, renal failure, myocardial infarction, and thrombocytopenia, reminiscent of other complement- mediated diseases. Multiple clinical and preclinical studies have implicated complement in the pathogenesis of COVID-19 illness. We previously found that the SARS-CoV-2 spike protein activates the alternative pathway of complement (APC) in vitro through interfering with the function of complement factor H, a key negative regulator of APC. Here, we demonstrated that serum from 58 COVID-19 patients (32 patients with minimal oxygen requirement, 7 on high flow oxygen, 17 requiring mechanical ventilation and 2 deaths) can induce complementmediated cell death in a functional assay (the modified Ham test) and increase membrane attack complex (C5b-9) deposition on the cell surface. A positive modified Ham assay (>20% cell-killing) was present in 41.2% COVID-19 patients requiring intubation (n=7/17) and only 6.3% in COVID-19 patients requiring minimal oxygen support (n=2/32). C5 and factor D inhibition effectively mitigated the complement amplification induced by COVID-19 patient serum. Increased serum factor Bb level was associated with disease severity in COVID-19 patients, suggesting that APC dysregulation plays an important role. Moreover, SARS-CoV-2 spike proteins directly block complement factor H from binding to heparin, which may lead to complement dysregulation on the cell surface. Taken together, our data suggest that complement dysregulation contributes to the pathogenesis of COVID-19 and may be a marker of disease severity.
登录
查看更多内容
影响因子：
64.5
作者：
Clausen, Thomas Mandel;Sandoval, Daniel R.;Esko, Jeffrey D.
通讯作者：
Esko, Jeffrey D.
影响因子：
7.3
作者：
Perkins SJ;Fung KW;Khan S
通讯作者：
Khan S
影响因子：
8.6
作者：
Mastaglio, Sara;Ruggeri, Annalisa;Ciceri, Fabio
通讯作者：
Ciceri, Fabio
影响因子：
64.8
作者：
Carvelli, Julien;Demaria, Olivier;Vivier, Eric
通讯作者：
Vivier, Eric
影响因子：
20.3
作者：
Chaturvedi, Shruti;Braunstein, Evan M.;Brodsky, Robert A.
通讯作者：
Brodsky, Robert A.