Systematic functional interrogation of SARS-CoV-2 host factors using Perturb-seq

Sara Sunshine, Andreas S. Puschnik, Joseph M. Replogle, Matthew T. Laurie, Jamin Liu, Beth Shoshana Zha, James K. Nuñez, Janie R. Byrum, Aidan H. McMorrow, Matthew B. Frieman, Juliane Winkler, Xiaojie Qiu, Oren S. Rosenberg, Manuel D. Leonetti, Chun Jimmie Ye, Jonathan S. Weissman (), Joseph L. DeRisi () and Marco Y. Hein ()
Additional contact information
Sara Sunshine: University of California San Francisco
Andreas S. Puschnik: San Francisco
Joseph M. Replogle: University of California, San Francisco
Matthew T. Laurie: University of California San Francisco
Jamin Liu: University of California San Francisco
Beth Shoshana Zha: University of California, San Francisco
James K. Nuñez: University of California, San Francisco
Janie R. Byrum: San Francisco
Aidan H. McMorrow: San Francisco
Matthew B. Frieman: University of Maryland School of Medicine
Juliane Winkler: University of California, San Francisco
Xiaojie Qiu: Whitehead Institute for Biomedical Research
Oren S. Rosenberg: University of California, San Francisco
Manuel D. Leonetti: San Francisco
Chun Jimmie Ye: University of California, San Francisco
Jonathan S. Weissman: Whitehead Institute for Biomedical Research
Joseph L. DeRisi: University of California San Francisco
Marco Y. Hein: San Francisco

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Genomic and proteomic screens have identified numerous host factors of SARS-CoV-2, but efficient delineation of their molecular roles during infection remains a challenge. Here we use Perturb-seq, combining genetic perturbations with a single-cell readout, to investigate how inactivation of host factors changes the course of SARS-CoV-2 infection and the host response in human lung epithelial cells. Our high-dimensional data resolve complex phenotypes such as shifts in the stages of infection and modulations of the interferon response. However, only a small percentage of host factors showed such phenotypes upon perturbation. We further identified the NF-κB inhibitor IκBα (NFKBIA), as well as the translation factors EIF4E2 and EIF4H as strong host dependency factors acting early in infection. Overall, our study provides massively parallel functional characterization of host factors of SARS-CoV-2 and quantitatively defines their roles both in virus-infected and bystander cells.

Date: 2023
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DOI: 10.1038/s41467-023-41788-4

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