Puray-Chavez Maritza, LaPak Kyle M, Schrank Travis P, Elliott Jennifer L, Bhatt Dhaval P, Agajanian Megan J, Jasuja Ria, Lawson Dana Q, Davis Keanu, Rothlauf Paul W, Jo Heejoon, Lee Nakyung, Tenneti Kasyap, Eschbach Jenna E, Mugisha Christian Shema, Vuong Hung R, Bailey Adam L, Hayes D Neil, Whelan Sean P J, Horani Amjad, Brody Steven L, Goldfarb Dennis, Major M Ben, Kutluay Sebla B
Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, MO, USA.
Department of Cell Biology and Physiology, Washington University in St. Louis, St. Louis, MO, USA.
bioRxiv. 2021 Mar 1:2021.03.01.433431. doi: 10.1101/2021.03.01.433431.
Established models for SARS-CoV-2 infection are limited and include cell lines of non-human origin and those engineered to overexpress ACE2, the cognate host cell receptor. We identified human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of ACE2. Infection of H522 cells required the SARS-CoV-2 spike protein, though in contrast to ACE2-dependent models, spike alone was not sufficient for H522 infection. Temporally resolved transcriptomic and proteomic profiling revealed alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type-I interferon signaling. Focused chemical screens point to important roles for clathrin-mediated endocytosis and endosomal cathepsins in SARS-CoV-2 infection of H522 cells. These findings imply the utilization of an alternative SARS-CoV-2 host cell receptor which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis.
已建立的新型冠状病毒感染模型有限，包括非人类来源的细胞系以及经过工程改造以过度表达同源宿主细胞受体血管紧张素转换酶2（ACE2）的细胞系。我们发现人H522肺腺癌细胞尽管完全缺乏ACE2，但对新型冠状病毒感染具有天然易感性。H522细胞的感染需要新型冠状病毒刺突蛋白，不过与依赖ACE2的模型不同，单独的刺突蛋白不足以使H522细胞感染。时间分辨转录组学和蛋白质组学分析揭示了细胞周期和抗病毒宿主细胞反应的改变，包括黑色素瘤分化相关蛋白5（MDA5）依赖的I型干扰素信号激活。针对性化学筛选表明网格蛋白介导的内吞作用和内体组织蛋白酶在新型冠状病毒感染H522细胞中起重要作用。这些发现意味着利用了一种替代性新型冠状病毒宿主细胞受体，这可能会影响新型冠状病毒的嗜性，进而影响人类疾病的发病机制。
