Mouse hepatitis virus (MHV) infection of laboratory mice occurs at high prevalence and impacts heavily on many biomedical disciplines in which mice are commonly used. Infection of lymphocyte donors with MHV results in T cell dysfunction, as reflected by in vitro proliferation and cytokine production. However, the role of cytokines in the pathogenesis of MHV infection after exposure of mice by natural routes has not been addressed. Once the role of these molecules has been firmly established, efforts will be made to identify the cell type(s) secreting cytokines and the cell type(s) upon which they act. The long-term goal is the development of rational strategies for control and prevention of enzootic MHV in laboratory mouse colonies.
The specific aims of the proposed research are: 1. to characterize further the role of cytokines in MHV pathogenesis, using cytokine immunotherapy or induction methods and cytokine deletion, and 2. to identify the cell types producing beneficial cytokines as well as those that are activated by these soluble mediators. The objective of the current proposal is to test the hypothesis that certain cytokines released by activated T cells, as well as other cell types, may mediate benign outcome of infection with MHV. Interferon gamma and interleukin 4 are the molecules of primary interest. Pilot data suggest that effector function of CD4+ T cells may be associated with pathology and negative outcome of MHV infection. These two aspects of T cell biology are difficult to separate; however, drug- and/or antibody-induced cell deletion combined with cytokine immunotherapy will begin to suggest whether our hypothesis has merit. The availability of genetically defined mice, recombinant cytokines, monoclonal antibodies reactive with these molecules and cell-specific drugs renders an approach to the in vivo interactions of virus and the immune system feasible.
