A Human Genome-wide CRISPR-Cas9 Screen Reveals Host Factors That Support Epstein-Barr Virus B cell infection

Wang, H.; Yeo, Y. Y.; wang, C.; Guo, R.; White, S.; Liao, Y.; Yiu, S.; Liu, G.; Huang, A.; Zhao, D. J.; Wang, Z.; Jiang, S.; Gewurz, B.; Zhao, B.

doi:10.64898/2026.09.28.754942

bioRxiv · 10.64898/2026.09.28.754942

A Human Genome-wide CRISPR-Cas9 Screen Reveals Host Factors That Support Epstein-Barr Virus B cell infection

Wang, H.·Yeo, Y. Y.·wang, C.·Guo, R.·White, S.·Liao, Y.·Yiu, S.·Liu, G.·Huang, A.·Zhao, D. J.·Wang, Z.·Jiang, S.·Gewurz, B.·Zhao, B.

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Abstract

Epstein-Barr virus (EBV) infects 90% of the population worldwide and is associated with multiple malignancies, including Burkitt, Hodgkin and post-transplant lymphomas, nasopharyngeal and gastric carcinoma. EBV also triggers autoimmune diseases, including multiple sclerosis and systemic lupus erythematosus. While host factors important for EBV B-cell entry have been defined, including CD21/CR2, MHC class II and R9AP, much remains to be learned about host factors that support post-entry steps of EBV infection. To gain insight, we conducted a human genome-wide CRISPR-Cas9 screen. In addition to known EBV B cell receptors/co-receptors, we identified multiple new factors and pathways essential for EBV B cell infection. These included multiple B cell signaling pathways, actin cytoskeleton and nuclear import factors. Knockout of CD19, its tetraspanin chaperone CD81 or karyopherin subunit alpha 1 (KPNA1, also called importin-5) significantly impaired establishment of EBV infection. EBV and CD19 co-localized at early stages of EBV infection, and the CD19 cytoplasmic tail was important for EBV infection, suggesting CD19 signaling supports EBV uptake. Depletion of KPNA1 significantly impaired establishment of EBV infection, but did not impair production of infectious EBV upon reactivation of latently infected B cells. Together, these results provide insights into pathways that support EBV B cell infection and identify potential therapeutic targets.

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Wang, H., Yeo, Y. Y., wang, C., Guo, R., White, S., Liao, Y., Yiu, S., Liu, G., Huang, A., Zhao, D. J., Wang, Z., Jiang, S., Gewurz, B., Zhao, B.. 2026-09-28. A Human Genome-wide CRISPR-Cas9 Screen Reveals Host Factors That Support Epstein-Barr Virus B cell infection. https://doi.org/10.64898/2026.09.28.754942

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