Pressure to evade cell-autonomous innate sensing reveals interplay between mitophagy, IFN signaling, and SARS-CoV-2 evolution.

SARS-CoV-2 emerged, and continues to evolve, to efficiently infect humans worldwide. SARS-CoV-2 evades early innate recognition, interferon signaling occurring only in bystander cells. How the virus continues to evolve in the face of innate responses has important consequences, but the pathways involved are incompletely understood. Here, we find that autophagy genes regulate innate immune signaling, impacting the basal set point of interferons and, thus, permissivity to infection. Mechanistically, autophagy (mitophagy) genes negatively regulate MAVS, and this low basal level of MAVS is efficiently antagonized by SARS-CoV-2 ORF9b, blocking interferon activation in infected cells. However, loss of autophagy increased MAVS and overcomes ORF9b-mediated antagonism. This has driven the evolution of SARS-CoV-2 to express more ORF9b, allowing SARS-CoV-2 to replicate under conditions of increased MAVS signaling. Altogether, we find a critical role of mitophagy in the regulation of innate immunity and uncover an evolutionary trajectory of SARS-CoV-2 ORF9b to overcome host defenses.