Cell-autonomous requirement for ACE2 across organs in lethal mouse SARS-CoV-2 infection.
Cell-autonomous requirement for ACE2 across organs in lethal mouse SARS-CoV-2 infection.
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DOI：
10.1371/journal.pbio.3001989
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发表时间：
2023-02
期刊：
影响因子：
9.8
通讯作者：
Kahn, Mark L.
中科院分区：
文献类型：
--
作者：
Tang, Alan T.;Buchholz, David W.;Szigety, Katherine M.;Imbiakha, Brian;Gao, Siqi;Frankfurter, Maxwell;Wang, Min;Yang, Jisheng;Hewins, Peter;Mericko-Ishizuka, Patricia;Leu, N. Adrian;Sterling, Stephanie;Monreal, Isaac A.;Sahler, Julie;August, Avery;Zhu, Xuming;Jurado, Kellie A.;Xu, Mingang;Morrisey, Edward E.;Millar, Sarah E.;Aguilar, Hector C.;Kahn, Mark L.
血管紧张素转换酶2(ACE2)是严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)的细胞表面受体。虽然它在冠状病毒病2019(新冠肺炎)发病机制中的核心作用是毋庸置疑的，但关于这种跨膜羧肽酶在疾病过程中的作用仍然存在重大争议。这些包括可溶性与膜结合的ACE2的作用，以及可能有助于病毒传播的ACE2非依赖性机制。测试这些角色需要活体模型。在这里，我们报告了人源化ACE2-Flosed小鼠和LSL-hACE2小鼠，其中hACE2从小鼠ACE2基因座表达，从而导致致命疾病并允许细胞特异性的Cre介导的功能丧失，以及LSL-hACE2小鼠，其中hACE2从rosa26基因座表达，使细胞特异性的Cre介导的功能获得。在暴露于SARS-CoV-2之后，携带hACE2基因的小鼠出现了致命性恶病质、肺渗透、血管内血栓形成和低氧血症--这些都是严重新冠肺炎的特征。Cre介导的hACE2的丢失和获得表明，在没有肺上皮感染的情况下，神经元感染会导致致死性恶病质、低氧血症和呼吸衰竭。在这一系列的基因实验中，我们证明了ACE2是SARS-CoV-2感染在嗅觉上皮、脑和肺中跨不同细胞类型绝对和细胞自主需要的。在这些不同部位抑制或阻断血管紧张素转换酶2的治疗可能是预防严重新冠肺炎的有效策略。具有人源化ACE2基因的新的小鼠遗传模型使细胞能够在体内剖析新冠肺炎的致病机制，揭示了ACE2对SARS-CoV-2感染在嗅上皮、脑和肺中跨不同细胞类型的绝对和细胞自主的需求。
Angiotensin-converting enzyme 2 (ACE2) is the cell-surface receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). While its central role in Coronavirus Disease 2019 (COVID-19) pathogenesis is indisputable, there remains significant debate regarding the role of this transmembrane carboxypeptidase in the disease course. These include the role of soluble versus membrane-bound ACE2, as well as ACE2-independent mechanisms that may contribute to viral spread. Testing these roles requires in vivo models. Here, we report humanized ACE2-floxed mice in which hACE2 is expressed from the mouse Ace2 locus in a manner that confers lethal disease and permits cell-specific, Cre-mediated loss of function, and LSL-hACE2 mice in which hACE2 is expressed from the Rosa26 locus enabling cell-specific, Cre-mediated gain of function. Following exposure to SARS-CoV-2, hACE2-floxed mice experienced lethal cachexia, pulmonary infiltrates, intravascular thrombosis and hypoxemia—hallmarks of severe COVID-19. Cre-mediated loss and gain of hACE2 demonstrate that neuronal infection confers lethal cachexia, hypoxemia, and respiratory failure in the absence of lung epithelial infection. In this series of genetic experiments, we demonstrate that ACE2 is absolutely and cell-autonomously required for SARS-CoV-2 infection in the olfactory epithelium, brain, and lung across diverse cell types. Therapies inhibiting or blocking ACE2 at these different sites are likely to be an effective strategy towards preventing severe COVID-19. New mouse genetic models with a humanized ACE2 locus enable cellular dissection of COVID-19 pathogenesis mechanisms in vivo, revealing the absolute and cell-autonomous requirement of ACE2 for SARS-CoV-2 infection in the olfactory epithelium, brain and lung across diverse cell types.
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DOI：
10.1126/science.abd3072
发表时间：
2020-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Daly JL;Simonetti B;Klein K;Chen KE;Williamson MK;Antón-Plágaro C;Shoemark DK;Simón-Gracia L;Bauer M;Hollandi R;Greber UF;Horvath P;Sessions RB;Helenius A;Hiscox JA;Teesalu T;Matthews DA;Davidson AD;Collins BM;Cullen PJ;Yamauchi Y
通讯作者：
Yamauchi Y
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：
29
作者：
Bartley CM;Johns C;Ngo TT;Dandekar R;Loudermilk RL;Alvarenga BD;Hawes IA;Zamecnik CR;Zorn KC;Alexander JR;Wapniarski AE;DeRisi JL;Francisco C;Nash KB;Wietstock SO;Pleasure SJ;Wilson MR
通讯作者：
Wilson MR
影响因子：
24.8
作者：
Fumagalli, Valeria;Rava, Micol;Marotta, Davide;Di Lucia, Pietro;Laura, Chiara;Sala, Eleonora;Grillo, Marta;Bono, Elisa;Giustini, Leonardo;Perucchini, Chiara;Mainetti, Marta;Sessa, Alessandro;Garcia-Manteiga, Jose M.;Donnici, Lorena;Manganaro, Lara;Delbue, Serena;Broccoli, Vania;De Francesco, Raffaele;D'Adamo, Patrizia;Kuka, Mirela;Guidotti, Luca G.;Iannacone, Matteo
通讯作者：
Iannacone, Matteo
影响因子：
16.6
作者：
Jain, Rajan;Barkauskas, Christina E.;Takeda, Norifumi;Bowie, Emily J.;Aghajanian, Haig;Wang, Qiaohong;Padmanabhan, Arun;Manderfield, Lauren J.;Gupta, Mudit;Li, Deqiang;Li, Li;Trivedi, Chinmay M.;Hogan, Brigid L. M.;Epstein, Jonathan A.
通讯作者：
Epstein, Jonathan A.