Uncovering the proviral role of B cell-intrinsic STAT1 expression during chronic gammaherpesvirus infection

Human gammaherpesviruses, such as Epstein Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV), are highly prevalent and are associated with several cancers, including B cell lymphomas. Although the risk factors underlying oncogenesis are not well understood, increased viral latency and viral reactivation likely precede the development of cancer. EBV and KSHV have a high degree of species- specificity which limits the ability to investigate these viruses, particularly during chronic infection in vivo. To overcome these limitations, we and others use murine gammaherpesvirus 68 (MHV68), a naturally occurring rodent gammaherpesvirus. MHV68 is genetically related to its human counterparts and shares pathogenic features, such as lymphomagenesis, B cell tropism, and the ability to hijack host germinal center responses for the establishment of chronic infection. MHV68 represents a powerful model to define host parameters that control chronic infection and viral lymphomagenesis in an intact host. Using the MHV68 model, we have discovered a proviral role of the B cell-intrinsic expression of STAT1, the effector protein of type I and type II interferon signaling, during chronic MHV68 infection. Specifically, B cell-specific STAT1 expression promoted the establishment of the latent splenic reservoir and virus-driven germinal center response that seeds lymphomagenesis. This project aims to determine the mechanism by which MHV68 usurps B cell-intrinsic STAT1 expression to establish chronic infection. Successful completion of the proposed studies will define the proviral mechanisms of B cell-intrinsic STAT1 expression during chronic MHV68 infection and provide insights into potential therapeutics to target chronic gammaherpesvirus infection and the development of associated cancers. Project Number: 1F31AI191670-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Erika Johansen | Institution: MEDICAL COLLEGE OF WISCONSIN, MILWAUKEE, WI | Award Amount: $49,538 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F07C-H (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F31AI19167001