The Role of Type I Interferon in Murine Roseolovirus Induced Autoimmune Gastritis

/ABSTRACT. Viral triggers of autoimmune disease remain poorly understood and have been hypothesized to contribute as initial triggers of the immune disturbances that underlie clinical autoimmunity as well as promoters of disease. Human Roseoloviruses, Human Herpesvirus (HHV)-6 and 7, have been associated with several autoimmune diseases notably encephalitis, and multiple sclerosis (MS). Due to high species-specific tropism, human herpesviruses are difficult to study in a controlled environment, and their relationship with the development of these disorders remains elusive. Recently however, the murine roseolovirus (MRV) was identified and found to be a close homolog of HHV-6 and 7. MRV is a thymotropic virus that causes transient, severe thymic atrophy with the most pronounced loss occurring in CD4/CD8 double-positive (DP) and CD4 single-positive (SP) thymocytes. Single-cell RNA sequencing data shows that CD4 SPs, DPs and double negative (DN) thymocytes as well as medullary thymic epithelial cells (mTECs) can support productive infection of MRV. Neonatal infection of mice with MRV causes autoimmune gastritis (AIG) in adulthood. CD4 T cells are both required and sufficient for AIG development in this model. MRV infections also results in loss of AIRE transcripts in mTECs, and development of autoantibodies to several tissue antigens targeting almost all organ systems. Additionally, type I interferon (IFN) signaling is required for development of AIG in neonatally infected mice. The goal of this study is to understand the role of type I IFN signaling in auto-immune gastritis development in the setting of neonatal MRV infection. We hypothesize that type I IFN is a major contributor in the disruption of central tolerance, specifically leading to alterations in T cell selection and development of autoreactive T cells, as well as an aberrant T regulatory cell (Treg) response. I will investigate whether type I IFN is required for the development of autoreactive T cells and whether type I IFN leads to disruptions in Treg development. Using a unique model of virus-induced autoimmunity, our study has the potential to shed light on the infectious triggers of the immune disturbances observed sometimes years prior to clinical symptoms, providing insight into the early mechanisms underlying autoimmune disease onset. As an MD/PhD student, my long-term goal is to become a physician-scientist leading a research lab in dermatology. Completion of this project will equip me with a strong foundation at the intersection of immunology, virology, and autoimmunity, fields that often converge in skin-related clinical presentations. My robust training plan at WashU in St Louis, one of the nation's leading MD/PhD programs integrates strong mentorship, rigorous coursework, independent study, and participation in research meetings ranging from local to international. This tailored approach is designed to support the successful execution of my research proposal and to position me for long-term success in achieving my career goals. Project Number: 1F30AI197461-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Ranya Guennoun | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $36,673 | Activity Code: F30 | Study Section: Special Emphasis Panel[ZRG1 F07B-C (21)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1F30AI19746101