High content screening and computational prediction reveal viral genes that suppress innate immune response

• Published in: bioRxiv
• Main Authors: Ng, Tai L, Olson, Erika J, Yoo, Tae Yeon, H Sloane Weiss, Koide, Yukiye, Koch, Peter D, Rollins, Nathan J, Mach, Pia, Meisinger, Tobias, Bricken, Trenton, Chang, Timothy Z, Molloy, Colin W, Zurcher, Jerome, Mitchison, Timothy, Glass, John I, Marks, Debora S, Way, Jeffrey C, Silver, Pamela A
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 15.12.2021
• Subjects: Biological activity; Computer applications; Genes; Immune response; Innate immunity; Interferon; Interferon regulatory factor 3; NF-κB protein; Nuclear transport; Plant virus diseases; Proteins; Transcription factors; Viral infections; Viruses
• DOI: 10.1101/2021.12.14.472572

Suppression of the host innate immune response is a critical aspect of viral replication. Upon infection, viruses may introduce one or more proteins that inhibit key immune pathways, such as the type I interferon pathway. However, the ability to predict and evaluate viral protein bioactivity on targeted pathways remains challenging and is typically done on a single virus/gene basis. Here, we present a medium-throughput high-content cell-based assay to reveal the immunosuppressive effects of viral proteins. To test the predictive power of our approach, we developed a library of 800 genes encoding known, predicted, and uncharacterized human viral genes. We find that previously known immune suppressors from numerous viral families such as Picornaviridae and Flaviviridae recorded positive responses. These include a number of viral proteases for which we further confirmed that innate immune suppression depends on protease activity. A class of predicted inhibitors encoded by Rhabdoviridae viruses was demonstrated to block nuclear transport, and several previously uncharacterized proteins from uncultivated viruses were shown to inhibit nuclear transport of the transcription factors NF-kB and IRF3. We propose that this pathway-based assay, together with early sequencing, gene synthesis, and viral infection studies, could partly serve as the basis for rapid in vitro characterization of novel viral proteins. Competing Interest Statement The authors have declared no competing interest.