ACE2 independent SARS-CoV-2 infection of a human lung cell line

In a screen of human upper airway cell lines, we identified the H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite no evidence of ACE2 or TMPRSS2 expression. Temporally resolved transcriptomic and proteomic profiling of H522 cells revealed consistent alterations in the antiviral host cell response, including marked 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. The natural permissiveness of H522 cells to SARS-CoV-2 infection despite no requirement for ACE2 implies the utilization of an alternative receptor and viral entry mechanism which may have important implications for SARS-CoV-2 pathogenesis in humans.