MNV-4, an Emerging Pathogen in Murine Models of Inflammatory Bowel Disease

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DESCRIPTION (provided by applicant): Murine norovirus (MNV) is emerging as a potential pathogen in mice. Initially, the virus appeared to cause morbidity and mortality only in immunocompromised mice while it did not cause any clinical signs of overt diseases in immunocompetent mice. However, we found that MNV infection can induce subtle changes in immune responses even in wild type mice and that the virus alters disease phenotypes in a mouse model of bacterially induced inflammatory bowel disease. Exacerbation of IBD by MNV was partly mediated by effects on dendritic cells. Additionally, we observed that MNV infection alters the production of several inflammatory cytokines in bone marrow derived macrophages. Thus, we suggest that MNV has potential to become a major interfering variable in research studies with rodents. Unfortunately, we do not have sufficient data to determine whether this virus should be eliminated from research facilities. For our proposed studies, we will focus on effects of MNV on mouse studies of IBD as we have significant experience with IBD research and we have evidence that MNV alters IBD development/progression. First, we will determine if and how MNV infection exacerbates IBD in three commonly used models of IBD. Next, we will determine if MNV alters antigen presentation and consequently immune responses to antigens in immunologically normal as well as immunologically deficient mice by altering DCs. Finally, we will determine if MNV alters immune responses by influencing DC and macrophage functions. Proposed studies in this application will fill the gap in current knowledge to determine whether the time and effort should be invested in elimination of MNV from the research facilities. Thus, our application is in line with the objective of current RFA to support investigation of "the impact of murine norovirus infection on immune response".