Influenza virus infection increases ACE2 expression and shedding in human small airway epithelial cells.
Influenza virus infection increases ACE2 expression and shedding in human small airway epithelial cells.
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DOI：
10.1183/13993003.03988-2020
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Petrache I
中科院分区：
文献类型：
--
作者：
Schweitzer KS;Crue T;Nall JM;Foster D;Sajuthi S;Correll KA;Nakamura M;Everman JL;Downey GP;Seibold MA;Bridges JP;Serban KA;Chu HW;Petrache I
由严重急性呼吸综合征冠状病毒2(SARS-CoV-2)引起的2019年冠状病毒病(新冠肺炎)患者与包括甲型流感在内的呼吸道病毒的混合感染率很高，这表明病原相互作用。我们研究了IAV如何增加新冠肺炎肺部疾病的风险，重点研究了受体血管紧张素转换酶2和蛋白酶TMPRSS2，它们在细胞内摄取SARS-CoV-2方面起到了协同作用。我们利用远端未患病肺组织匀浆的单细胞RNA测序发现，在基线水平，ACE2在小气道的基底、杯状、纤毛和分泌上皮细胞中表达最低。我们专注于人类小气道上皮细胞(SAECs)，这是病毒感染后肺损伤发病机制的核心。来自顶端感染IAV(高达3×105pfu；~1个感染复数)的未患病供者肺的原代SAECs显著(8倍)促进ACE2的表达，与病毒激活的转录因子STAT1的表达平行。IAV增加了细胞内ACE2的表观电泳率，并在顶端分泌物中产生了一段ACE2片段(90 KDa)，表明该受体被切割。此外，IAV还增加了ACE2、脱落酶ADAM17(TACE)和TMPRSS2的表达，增加了TMPRSS2酶原及其成熟片段的表达，提示蛋白水解性自我激活。这些结果表明，IAV放大了SARS-CoV-2感染远端肺所必需的分子的表达。此外，IAV对ACE2的翻译后改变可能会增加对肺损伤的易感性，例如在病毒合并感染期间发生的急性呼吸窘迫综合征。这些发现支持了在新冠肺炎大流行期间预防和治疗流感感染的努力。流感病毒感染小气道内的细胞增加了SARS-CoV-2感染所需分子的表达，这种方式预示着同时感染流感和冠状病毒https://bit.ly/3nu1WAo的人肺部疾病的严重性增加。
Patients with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) demonstrate high rates of co-infection with respiratory viruses, including influenza A (IAV), suggesting pathogenic interactions. We investigated how IAV may increase the risk of COVID-19 lung disease, focusing on the receptor angiotensin-converting enzyme (ACE)2 and the protease TMPRSS2, which cooperate in the intracellular uptake of SARS-CoV-2. We found, using single-cell RNA sequencing of distal human nondiseased lung homogenates, that at baseline, ACE2 is minimally expressed in basal, goblet, ciliated and secretory epithelial cells populating small airways. We focused on human small airway epithelial cells (SAECs), central to the pathogenesis of lung injury following viral infections. Primary SAECs from nondiseased donor lungs apically infected (at the air-liquid interface) with IAV (up to 3×105 pfu; ~1 multiplicity of infection) markedly (eight-fold) boosted the expression of ACE2, paralleling that of STAT1, a transcription factor activated by viruses. IAV increased the apparent electrophoretic mobility of intracellular ACE2 and generated an ACE2 fragment (90 kDa) in apical secretions, suggesting cleavage of this receptor. In addition, IAV increased the expression of two proteases known to cleave ACE2, sheddase ADAM17 (TACE) and TMPRSS2 and increased the TMPRSS2 zymogen and its mature fragments, implicating proteolytic autoactivation. These results indicate that IAV amplifies the expression of molecules necessary for SARS-CoV-2 infection of the distal lung. Furthermore, post-translational changes in ACE2 by IAV may increase vulnerability to lung injury such as acute respiratory distress syndrome during viral co-infections. These findings support efforts in the prevention and treatment of influenza infections during the COVID-19 pandemic. Influenza virus infection of cells lining the small airways increases the expression of molecules required for SARS-CoV-2 uptake in a manner that predicts increased severity of lung disease in those co-infected with influenza and coronaviruses https://bit.ly/3nu1WAo
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影响因子：
64.5
作者：
Hou, Yixuan J.;Okuda, Kenichi;Baric, Ralph S.
通讯作者：
Baric, Ralph S.
影响因子：
5.4
作者：
Heurich, Adeline;Hofmann-Winkler, Heike;Poehlmann, Stefan
通讯作者：
Poehlmann, Stefan
影响因子：
6.7
作者：
Hatesuer B;Bertram S;Mehnert N;Bahgat MM;Nelson PS;Pöhlmann S;Schughart K
通讯作者：
Schughart K
DOI：
10.1007/s00018-007-6228-6
发表时间：
2007-08
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Imai Y;Kuba K;Penninger JM
通讯作者：
Penninger JM
影响因子：
5.4
作者：
Glowacka, Ilona;Bertram, Stephanie;Poehlmann, Stefan
通讯作者：
Poehlmann, Stefan