The innate immune response to virus infection has a strong influence on virus infection in the brain and the clinical outcome of disease. Our studies have focused on two animal models of virus-mediated neuropathogenesis to determine the host response proteins that regulate disease induction for virus replication and viral pathogenesis. In FY2015, we primarily focused on examining the mechanisms responsible for bunyavirus entry into the CNS. Neuroinvasion is a key mediator of viral encephalitis and identifying the mechanisms of neuroinvasion would allow therapeutic targeting to inhibit virus entry to the CNS during the viremia stages of infection. In this study, we analyzed the mechanism of neuroinvasion of La Crosse Virus (LACV), a bunyavirus that is the leading cause of pediatric viral encephalitis in the USA. We found that capillaries in specific regions in the brain, most notably the olfactory bulb (OB), were more sensitive to virus-induced vascular leak and crossing of virus-sized particles than capillaries in other brain regions. These OB capillaries were important for neuroinvasion as OB removal reduced virus-induced disease. Analysis of OB capillaries showed specific alterations in cytoskeletal and Rho GTPase protein expression not observed in capillaries from other brain areas where leakage did not occur. Thus, LACV neuroinvasion occurs through hematogenous spread in specific brain regions, where capillaries are more prone to virus-induced activation. These regions may be hot-spots not only for LACV neuroinvasion, but other neurovirulent viruses. (Winkler et al. Acta Neuropath. 2015)
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