Genome-wide CRISPR screen reveals host genes that regulate SARS-CoV-2 infection
Jin WeiiD, Mia Madel AlfajaroiD, Ruth E. HannaiD, Peter C. DeWeirdtiD, Madison S. StrineiD, William J. Lu-CulliganiD, Shang‐Min ZhangiD, Vincent R. GrazianoiD, Cameron O. SchmitziD, Jennifer CheniD, Madeleine C. MankowskiiD, Renata B. FilleriD, Victor GasqueiD, Fernando de Miguel, Huacui CheniD, Kasopefoluwa Y. OguntuyoiD, Laura AbriolaiD, Yulia V. SurovtsevaiD, Robert C. OrchardiD, Benhur LeeiD, Brett D. LindenbachiD, Katerina A. PolitiiD, David van DijkiD, Matthew D. SimoniD, Qin YaniD, , Craig B. WileniD
Abstract
Identification of host genes essential for SARS-CoV-2 infection may reveal novel therapeutic targets and inform our understanding of COVID-19 pathogenesis. Here we performed a genome-wide CRISPR screen with SARS-CoV-2 and identified known SARS-CoV-2 host factors including the receptor ACE2 and protease Cathepsin L. We additionally discovered novel pro-viral genes and pathways including the SWI/SNF chromatin remodeling complex and key components of the TGF-{beta} signaling pathway. Small molecule inhibitors of these pathways prevented SARS-CoV-2-induced cell death. We also revealed that the alarmin HMGB1 is critical for SARS-CoV-2 replication. In contrast, loss of the histone H3.3 chaperone complex sensitized cells to virus-induced death. Together this study reveals potential therapeutic targets for SARS-CoV-2 and highlights host genes that may regulate COVID-19 pathogenesis.
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Abstract summary
Claude Opus 5.5 · xhigh effort · 18 Oct 2026 · from the abstract · CC BY-NC-ND 4.0
A genome-wide CRISPR screen with SARS-CoV-2 recovers ACE2 and Cathepsin L and nominates SWI/SNF, TGF-beta signalling and HMGB1 as pro-viral; pathway inhibitors blocked virus-induced death.
Host genes the virus depends on are drug targets that sit outside the viral genome, so a screen that names them feeds both therapeutic work and models of COVID-19 pathogenesis. Alongside the expected entry machinery, this screen points at chromatin remodelling and TGF-beta signalling, and follows the hits with small molecule inhibition in cells.
Key results
ClaimedThe screen re-identified established entry factors and added pro-viral genes acting through chromatin remodelling and growth-factor signalling, with the alarmin HMGB1 required for viral replication.
Known hits recovered were the receptor ACE2 and the protease Cathepsin L; newly reported pro-viral hits were the SWI/SNF chromatin remodeling complex, key components of TGF-beta signalling, and HMGB1. No enrichment scores, hit counts or screen thresholds appear in the abstract. · Abstract
ClaimedPharmacological inhibition of the newly nominated pathways protected cells from death caused by SARS-CoV-2 infection.
Small molecule inhibitors of the SWI/SNF and TGF-beta pathways are reported to prevent virus-induced cell death; the compounds, doses and magnitude of protection are not given. · Abstract
ClaimedNot all hits were pro-viral: losing the histone H3.3 chaperone complex made cells more vulnerable to virus-induced death.
Reported as the opposite direction of effect to the pro-viral hits; no survival measurements, replication data or effect sizes accompany the statement. · Abstract
Methods, data and reproducibility
A genome-wide CRISPR screen run in cultured cells infected with SARS-CoV-2 to identify host genes affecting infection, followed by treatment with small molecule inhibitors of the pathways the screen nominated.
- genome-wide CRISPR screen in cells infected with SARS-CoV-2 · SARS-CoV-2; host cells not specified
- Methods & tools
- genome-wide CRISPR screen
Limitations (2)
- No screen statistics are reported: the cell line, the guide library, the number of hits and any score or significance threshold are all absent, so the confidence behind each nomination is unknown. · noted in this summary
- The rescue by small molecule inhibitors is described without naming the compounds, their concentrations or the size of the protection, and without separating effects on viral replication from effects on cell survival. · noted in this summary
Who should read:Read this if you study SARS-CoV-2 host dependency factors and want candidate chromatin-remodelling and TGF-beta pathway targets to follow up.
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