Recombinant ACE2 Expression Is Required for SARS-CoV-2 To Infect Primary Human Endothelial Cells and Induce Inflammatory and Procoagulative Responses.
Recombinant ACE2 Expression Is Required for SARS-CoV-2 To Infect Primary Human Endothelial Cells and Induce Inflammatory and Procoagulative Responses.
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DOI：
10.1128/mbio.03185-20
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发表时间：
2020-12-11
期刊：
影响因子：
6.4
通讯作者：
Mackow ER
中科院分区：
文献类型：
--
作者：
Nascimento Conde J;Schutt WR;Gorbunova EE;Mackow ER
SARS-CoV-2通过ACE2受体感染肺上皮细胞并引起ARDS。COVID-19可导致渐进性呼吸衰竭，导致弥漫性肺泡损伤和全身性凝血功能障碍、血栓形成和毛细血管炎症，这些都与肺泡对EC功能障碍的反应有关。SARS-CoV-2引起COVID-19，这是一种以肺水肿、病毒性肺炎、多器官功能障碍、凝血功能障碍和炎症为特征的急性呼吸窘迫综合征（ARDS）。SARS-CoV-2利用血管紧张素转换酶2 （ACE2）受体感染和损伤上呼吸道纤毛上皮细胞。在肺泡中，气体交换通过上皮-内皮屏障发生，该屏障将呼吸与内皮细胞（EC）对水肿、凝血和炎症的调节联系起来。SARS-CoV-2如何失调血管功能导致COVID-19患者ARDS仍然是一个谜，主要集中在失调的EC反应上。SARS-CoV-2是否直接或间接影响内皮功能仍有待解决，这对了解SARS-CoV-2的发病机制和治疗靶点至关重要。我们证明，原代人ECs在蛋白质和RNA水平上缺乏ACE2受体，并且SARS-CoV-2不能直接感染来自肺、心脏、脑、脐静脉或肾脏组织的ECs。相反，用重组ACE2受体转导的肺ECs被SARS-CoV-2感染，导致高病毒滴度（~ 1 × 107/ml）、多核合胞体和EC裂解。SARS-CoV-2感染表达ace2的ECs可引起COVID-19患者的促凝反应和炎症反应。SARS-CoV-2不能直接感染和溶解无ACE2表达的ECs，解释了COVID-19患者缺乏血管出血的原因，表明内皮不是SARS-CoV-2感染的主要目标。这些发现与SARS-CoV-2间接激活调节COVID-19患者血栓形成和内皮炎的EC程序一致，并将治疗策略集中在靶向上皮和炎症反应上，这些反应可激活内皮或启动有限的ace2非依赖性EC感染。
SARS-CoV-2 infects pulmonary epithelial cells through ACE2 receptors and causes ARDS. COVID-19 causes progressive respiratory failure resulting from diffuse alveolar damage and systemic coagulopathy, thrombosis, and capillary inflammation that tie alveolar responses to EC dysfunction. SARS-CoV-2 causes COVID-19, an acute respiratory distress syndrome (ARDS) characterized by pulmonary edema, viral pneumonia, multiorgan dysfunction, coagulopathy, and inflammation. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) receptors to infect and damage ciliated epithelial cells in the upper respiratory tract. In alveoli, gas exchange occurs across an epithelial-endothelial barrier that ties respiration to endothelial cell (EC) regulation of edema, coagulation, and inflammation. How SARS-CoV-2 dysregulates vascular functions to cause ARDS in COVID-19 patients remains an enigma focused on dysregulated EC responses. Whether SARS-CoV-2 directly or indirectly affects functions of the endothelium remains to be resolved and is critical to understanding SARS-CoV-2 pathogenesis and therapeutic targets. We demonstrate that primary human ECs lack ACE2 receptors at protein and RNA levels and that SARS-CoV-2 is incapable of directly infecting ECs derived from pulmonary, cardiac, brain, umbilical vein, or kidney tissues. In contrast, pulmonary ECs transduced with recombinant ACE2 receptors are infected by SARS-CoV-2 and result in high viral titers (∼1 × 107/ml), multinucleate syncytia, and EC lysis. SARS-CoV-2 infection of ACE2-expressing ECs elicits procoagulative and inflammatory responses observed in COVID-19 patients. The inability of SARS-CoV-2 to directly infect and lyse ECs without ACE2 expression explains the lack of vascular hemorrhage in COVID-19 patients and indicates that the endothelium is not a primary target of SARS-CoV-2 infection. These findings are consistent with SARS-CoV-2 indirectly activating EC programs that regulate thrombosis and endotheliitis in COVID-19 patients and focus strategies on therapeutically targeting epithelial and inflammatory responses that activate the endothelium or initiate limited ACE2-independent EC infection.