The Host Response to Venezuelan Equine Encephalitis Virus

Viruses are currently the most common cause of encephalitis. Arboviruses in the Alphavirus genus in the family Togaviridae contain multiple viruses capable of causing human encephalitis. Of these, VEEV represents the most significant human pathogen. However, no licensed vaccines or therapeutics are available. A comprehensive understanding of the host response to a pathogen is integral in the development of both. By using intranasal infection with TC83, the vaccine attenuated strain of VEEV, we are able to mimic VEEV encephalitis as well as evaluate the vaccine candidate. Intranasal infection with TC83 in different mouse strains led to development of three models of infection: (1) non-lethal infection with complete viral clearance from the brain in C57BL/6 mice (2) lethal infection in C3H/HeN mice and (3) persistent viral infection of the brain in α/β T-cell receptor deficient (TCR KO) mice. All three strains display a similar viral kinetic and brain pathology. Further comparison of the host response among these models derived key immune mediated factors in protection and pathogenesis. Proinflammatory cytokine kinetics and levels in the brain differentiate lethal (BL6) and non-lethal infection (C3H). Furthermore, significant differences in gene transcription in the brain appeared between strains. These factors indicated a role for natural killer cells in pathogenesis. Subsequent loss and gain of function studies in the natural killer cell compartment in C3H mice demonstrated a pathogenic role for this cell type. In TCR KO mice, αβ T-cells appear to be required for clearance of virus, but are not needed to prevent lethal infection as virus persists in the brain for 90 days post-infection. Histological signs of inflammation remain to 30 days post-infection. In addition, MCP-1, RANTES, and IL-12p40 levels remain elevated above controls to 90 days post-infection. These cytokines may be useful in the identification of viral infection without requiring isolation of the virus. Loss and gain of function studies in BL6 mice indicate that IL-12p40 appears to aid in recovery early in infection of BL6 mice, but may enhance pathogenesis later in infection. In addition, in a model of virulent VEEV encephalitis, IL-12p40 appears to be pathogenic as vaccinated mice recover more rapidly in the absence of IL-12p40. However, this effect is dependent on the presence of adoptively transferred antigen-specific T-cells. In summary, C3H mice survive in the absence of functional NK cells indicating the importance of this cell population. T-cells in BL6 are not required for survival, and absence of T-cells establishes chronic infection with a detectable chronic host response. This establishes a novel model to study T-cells in viral clearance as well as the chronic responses to infection in the brain.