SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery.
SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery.
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DOI：
10.1016/j.celrep.2021.109055
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发表时间：
2021-05-04
期刊：
影响因子：
8.8
通讯作者：
Stripp BR
中科院分区：
文献类型：
--
作者：
Mulay A;Konda B;Garcia G Jr;Yao C;Beil S;Villalba JM;Koziol C;Sen C;Purkayastha A;Kolls JK;Pociask DA;Pessina P;de Aja JS;Garcia-de-Alba C;Kim CF;Gomperts B;Arumugaswami V;Stripp BR
2019年冠状病毒病(新冠肺炎)是由严重急性呼吸综合征相关冠状病毒2型(SARS-CoV-2)引起的最新一次呼吸道大流行。虽然感染始于近端呼吸道，但严重的、有时是致命的症状是由远端肺的肺泡2型(AT2)细胞感染和相关的炎症引起的。在这项研究中，我们建立了原代人肺上皮细胞感染模型，以了解近端和远端肺上皮对SARS-CoV-2感染的初始反应。近端呼吸道上皮细胞的分化气液界面(ALI)培养和远端肺AT2细胞的肺泡球培养容易被SARS-CoV-2感染，导致上皮细胞自主的促炎反应，干扰素信号基因表达增加。对选定的新冠肺炎候选药物疗效的验证研究证实，瑞希韦可强烈抑制病毒感染/复制。我们为新冠肺炎的病理生物学研究以及针对SARS-CoV-2和呼吸道紧急病原体的快速药物筛选提供了相关平台。在人肺上皮的体外模型中，包括近远轴的不同类型的细胞，对于模拟感染是至关重要的。Mulay等人。研究表明，肺泡球上皮样细胞为2型和1型，被SARS-CoV-2感染，启动干扰素反应，并作为筛选抗病毒药物的平台。
Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Although infection initiates in the proximal airways, severe and sometimes fatal symptoms of the disease are caused by infection of the alveolar type 2 (AT2) cells of the distal lung and associated inflammation. In this study, we develop primary human lung epithelial infection models to understand initial responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface (ALI) cultures of proximal airway epithelium and alveosphere cultures of distal lung AT2 cells are readily infected by SARS-CoV-2, leading to an epithelial cell-autonomous proinflammatory response with increased expression of interferon signaling genes. Studies to validate the efficacy of selected candidate COVID-19 drugs confirm that remdesivir strongly suppresses viral infection/replication. We provide a relevant platform for study of COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and emergent respiratory pathogens. In vitro models of human lung epithelium, including diverse cell types of the proximo-distal axis, are critical for modeling infection. Mulay et al. show that alveospheres, with epithelial type 2- and type 1-like cells, are infected by SARS-CoV-2, initiating an interferon response, and serve as a platform for screening antiviral drugs.
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