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We identify STAT3 as a critical host determinant of gammaherpesvirus (YHV) pathogenesis in the murid host.Signal transducer and activator of transcription-3 (STAT3) responds to cytokines in the microenvironment of the cell to orchestrate effector responses such as proliferation, inflammation, metastasis, and developmental programming of the cell.STAT3 is constitutively active in many cancers including those associated with KSHV and EBV infection.