ORAI1 establishes resistance to SARS-CoV-2 infection by regulating tonic type I interferon signaling.

ORAI1 and STIM1 are the critical mediators of store-operated Ca entry by acting as the pore subunit and an endoplasmic reticulum-resident signaling molecule, respectively. In addition to Ca signaling, STIM1 is also involved in regulation of a cytosolic nucleic acid sensing pathway. Using and knockout cells, we examined their contribution to the host response to SARS-CoV-2 infection. knockout cells showed strong resistance to SARS-CoV-2 infection due to enhanced type I interferon response. On the contrary, knockout cells showed high susceptibility to SARS-CoV-2 infection as judged by increased expression of viral proteins and a high viral load. Mechanistically, knockout cells showed reduced homeostatic cytoplasmic Ca concentration and severe impairment in tonic interferon signaling. Transcriptome analysis showed downregulation of multiple cellular defense mechanisms, including antiviral signaling pathways in ORAI1 knockout cells, which are likely due to reduced expression of the Ca -dependent transcription factors of the activator protein 1 (AP-1) family and . Our results identify a novel role of ORAI1-mediated Ca signaling in regulating the baseline type I interferon level, which is a determinant of host resistance to SARS-CoV-2 infection.