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

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.

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.