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ISG15-Mediated Suppression of Type I Interferon Signaling Leads to Susceptibility to Epstein-Barr Virus Infection (Early_Infection_day7_BulkRNAseq)

ABSTRACT: Epstein-Barr Virus (EBV), the first identified human oncogenic virus, is linked to numerous malignancies, including gastric cancer, nasopharyngeal cancer and multiple B-cell Lymphomas. However, the host-virus interactions that regulate EBV-driven cell transformation and pathogenesis remain incompletely understood. Here, employing a Cas9–ribonucleoprotein (RNP)-based screen in primary B cells, we identified 11 host factors that promote and 35 that restrict EBV-driven outgrowth. Notably, ISG15, a ubiquitin-like, type I interferon-induced antiviral protein, exhibited a dependency role for growth in early stages of infection but not in LCLs. Mechanistically, we found that the regulation of free ISG15 levels greatly impacts the proliferation capacity of EBV-infected B-cells, by modulating the activation of type I IFN signaling. Finally, we identified rare germ-line variants in UBA7, the ISG15 E1 enzyme, in patients with EBV severe disorders, that impair the ISG15 conjugation process. This highlights a critical role of ISG15 in the control of EBV infections.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298096 | GEO | 2025/05/29

REPOSITORIES: GEO

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