High-content screening of coronavirus genes for innate immune suppression reveals enhanced potency of SARS-CoV-2 proteins

Olson, Erika J.; Brown, David M.; Chang, Timothy Z.; Ding, Lin; Ng, Tai L.; Weiss, H. Sloane; Koide, Yukiye; Koch, Peter; Rollins, Nathan; Mach, Pia; Meisinger, Tobias; Bricken, Trenton; Rollins, Joshua; Zhang, Yun; Molloy, Colin; Queenan, Bridget N.; Mitchison, Timothy; Marks, Debora; Way, Jeffrey C.; Glass, John I.; Silver, Pamela A.

Suppression of the host intracellular innate immune system is an essential aspect of viral replication. Here, we developed a suite of medium-throughput high-content cell-based assays to reveal the effect of individual coronavirus proteins on antiviral innate immune pathways. Using these assays, we screened the 196 protein products of seven coronaviruses (SARS-CoV-2, SARS-CoV-1, 229E, NL63, OC43, HKU1 and MERS). This includes a previously unidentified gene in SARS-CoV-2 encoded within the Spike gene. We observe immune-suppressing activity in both known host-suppressing genes (e.g., NSP1, Orf6, NSP3, and NSP5) as well as other coronavirus genes, including the newly identified SARS-CoV-2 protein. Moreover, the genes encoded by SARS-CoV-2 are generally more potent immune suppressors than their homologues from the other coronaviruses. This suite of pathway-based and mechanism-agnostic assays could serve as the basis for rapid in vitro prediction of the pathogenicity of novel viruses based on provision of sequence information alone.