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

The National Institute of Allergy and Infectious Diseases awarded The Medical College of Wisconsin, Inc., $247,138 on September 30, 2025, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate the proviral role of B cell-intrinsic STAT1 expression during chronic gammaherpesvirus infection.

The research uses murine gammaherpesvirus 68 (MHV68), a naturally occurring rodent gammaherpesvirus genetically related to human counterparts including Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. The project aims to determine the mechanism by which MHV68 usurps B cell-intrinsic STAT1 expression—the effector protein of type I and type II interferon signaling—to establish chronic infection and promote virus-driven germinal center responses that seed lymphomagenesis. Prior work discovered that B cell-specific STAT1 expression promotes establishment of the latent splenic reservoir in chronic MHV68 infection. Successful completion will define proviral mechanisms of B cell-intrinsic STAT1 during chronic MHV68 infection and provide insights into potential therapeutics targeting chronic gammaherpesvirus infection and associated cancers.

The award period runs from September 30, 2025, through March 31, 2028, with place of performance in Wauwatosa, Wisconsin. The project is classified as a Project Grant, an assistance type supporting biomedical research and research training in infectious diseases and related areas at public and private nonprofit institutions.

Abstract

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.