Redundant and distinct mechanisms suppress innate immune activation during SARS-CoV-2 infection

by Fuchun Zhou, Sivakumar Periasamy, Nathaniel D. Jackson, Wan Sze Cheng, Ruben Soto Acosta, Aarti Tripathi, Kritika Kedarinath, Philipp A. Ilinykh, Chengjin Ye, Shailendra Chauhan, German Nudelman, Elena Zaslavsky, Haiping Hao, Steven G. Widen, Luis Martinez-Sobrido, Stuart C. Sealfon, Alexander Bukreyev Several SARS-CoV-2 proteins have been shown to counteract the host innate immune response, mostly using in vitro protein expression, which may not fully reflect their role in the context of viral infection. In addition, while each viral protein was characterized in a different experimental system, its relative contribution to immunosuppression remains unclear. Here we used a SARS-CoV-2 bacterial artificial chromosome with en passant mutagenesis to recover a panel of 12 infectious recombinant SARS-CoV-2 viruses, each with mutations in either NSP1, NSP2, NSP3, NSP6, NSP12, NSP13, NSP14, NSP15, NSP16, ORF3a, ORF6, or ORF8. We used the interferon-stimulated response element (ISRE)-driven