Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell
Year: 2021
Type: article
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) variants govern transmissibility, responsiveness to vaccination, and disease severity. In a screen for new models of SARS-CoV-2 infection, we identify human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of angiotensin-converting enzyme 2 (ACE2) expression. Remarkably, H522 infection requires the E484D S variant; viruses expressing wild-type S are not infectious. Anti-S monoclonal antibodies differentially neutralize SARS-CoV-2 E484D S in H522 cells as compared to ACE2-expressing cells. Sera from vaccinated individuals block this alternative entry mechanism, whereas convalescent sera are less effective. Although the H522 receptor remains unknown, depletion of surface heparan sulfates block H522 infection. Temporally resolved transcriptomic and proteomic profiling reveal alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type I interferon signaling. These findings establish an alternative SARS-CoV-2 host cell receptor for the E484D SARS-CoV-2 variant, which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis.
Source: Cell Reports
Authors: Maritza Puray-Chavez, Kyle M. LaPak, Travis P. Schrank, Jennifer L. Elliott, Dhaval P. Bhatt, Megan J. Agajanian, Ria Jasuja, Dana Q. Lawson, Keanu Davis, Paul W. Rothlauf, Zhuoming Liu, Heejoon Jo, Nakyung Lee, Kasyap Tenneti, Jenna E. Eschbach, Christian Shema Mugisha, Emily M. Cousins, Erica W. Cloer, Hung R. Vuong, Laura A. VanBlargan, Adam L. Bailey, Pavlo Gilchuk, James E. Crowe, Michael S. Diamond, D. Neil Hayes, Sean P.J. Whelan, Amjad Horani, Steven L. Brody, Dennis Goldfarb, M. Ben Major, Sebla B. Kutluay
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: V Foundation for Cancer Research, AstraZeneca, Vanderbilt University, Takeda Pharmaceuticals U.S.A., University of Washington, Alvin J. Siteman Cancer Center, National Institutes of Health, Defense Advanced Research Projects Agency, Washington University School of Medicine in St. Louis, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Dental and Craniofacial Research, National Center for Advancing Translational Sciences
Awards: Human antibody-based countermeasures against the Wuhan Coronavirus SARS-CoV-2, G1382039244, G1389837536, G1978056178, The Role of Dynein Motor Mutations in Motile Cilia Disease, RNA Processing in Non-Segmented Minus-Strand RNA Viruses, Mechanisms Determining Dysregulation of the NRF2 Oxidative Stress Response in Head and Neck Squamous Cell Carcinoma, G6120206497, Multidisciplinary research training in pulmonary diseases, G6400721970, G6717649131, The Role of Protein Kinases in NRF2-driven Lung Squamous Cell Carcinoma, G7821046820, G7846559677, RNA Processing in Non-Segmented Minus-Strand RNA Viruses, G9000006824, G9000203450, TRAINING IN THE IMMUNOBIOLOGY AND MOLECULAR CELL BIOLOGY OF CANCER, Washington University Institute of Clinical and Translational Sciences, Cancer Center Support Grant
OpenAlex ID: W3175341024