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

• Published in: bioRxiv 2021-03
• Main Authors: Olson, Erika J, Brown, David M, Chang, Timothy Z, Ding, Lin, Ng, Tai L, H Sloane Weiss, 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
• Format: Article
• Language: English
• Subjects: Coronaviridae; Coronaviruses; Genes; Immune system; Innate immunity; Pathogenicity; Severe acute respiratory syndrome coronavirus 2
• DOI: 10.1101/2021.03.02.433434

Summary 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. Competing Interest Statement The authors have declared no competing interest. Footnotes * ↵* Co-first authors * ↵** Lead contact