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. ABSTRACT 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 × 10 7 /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.
【저자키워드】 COVID-19, SARS-CoV-2, Inflammation, ACE2, pulmonary, Endotheliitis, Coagulopathy, endothelial cells, 【초록키워드】 ARDS, thrombosis, SARS-COV-2 infection, Infection, ACE2 receptor, angiotensin-converting enzyme 2, Brain, Endothelium, RNA, Coagulation, Viral pneumonia, Protein, response, Gas exchange, Syncytia, edema, Pulmonary edema, Diffuse alveolar damage, receptor, ACE2 expression, epithelial, Critical, upper respiratory tract, SARS-CoV-2 pathogenesis, function, therapeutic targets, COVID-19 patients, acute respiratory distress, Endothelial cell, Inflammatory response, regulate, Multiorgan dysfunction, COVID-19 patient, hemorrhage, pulmonary epithelial cell, dysfunction, Regulation, Vascular, syndrome, kidney tissues, progressive respiratory failure, recombinant ACE2, Vascular function, alveolar, viral titer, infecting, infect, Affect, responses, resulting, lack, characterized, indicate, occur, elicit, cause, activate, dysregulated, explain, resolved, activating, transduced, ciliated epithelial cell, umbilical, 【제목키워드】 Human, response, recombinant,