Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell

Puray-Chavez, M.; Lapak, K. M.; Schrank, T. P.; Elliott, J. L.; Bhatt, D. P.; Agajanian, M. J.; Jasuja, R.; Lawson, D. Q.; Davis, K.; Rothlauf, P. W.; Jo, H.; Lee, N.; Tenneti, K.; Eschbach, J. E.; Shema Mugisha, C.; Vuong, H. R.; Bailey, A. L.; Hayes, D. N.; Whelan, S. P. J.; Horani, A.; Brody, S. L.; Goldfarb, D.; Major, M. B.; Kutluay, S. B.

doi:10.1101/2021.03.01.433431

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bioRxiv · 10.1101/2021.03.01.433431

Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell

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Abstract

Established in vitro 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.

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Puray-Chavez, M., Lapak, K. M., Schrank, T. P., Elliott, J. L., Bhatt, D. P., Agajanian, M. J., Jasuja, R., Lawson, D. Q., Davis, K., Rothlauf, P. W., Jo, H., Lee, N., Tenneti, K., Eschbach, J. E., Shema Mugisha, C., Vuong, H. R., Bailey, A. L., Hayes, D. N., Whelan, S. P. J., Horani, A., Brody, S. L., Goldfarb, D., Major, M. B., Kutluay, S. B.. 2021-03-01. Systematic analysis of SARS-CoV-2 infection of an ACE2-negative human airway cell. https://doi.org/10.1101/2021.03.01.433431

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