Present Research: My postdoctoral research in Neurovirology Laboratory at the University of Minnesota specifically investigates the role of central nervous system (CNS)-infiltrating peripheral immune cells in driving chronic activation of brain-resident glia and its associated neurotoxicity. Potent immune responses are critical to enhance pathogen clearance, but prolonged responses following neuroinflammation can be detrimental to brain tissue. Dysregulated chronic immune activation and immune cell infiltration promote analogous nerve damage and neurotoxicity. For this reason, immunomodulation of neurotoxic, recall response-driven inflammation in response to CSF viral escape is clearly a promising adjunctive therapy in mitigating neural damage. We found that CNS-infiltrating CD8 T-cells differentiate into several distinct subsets. Tissue resident memory (TRM) CD8 T-cells are one of these unique subsets that develop following resolution of primary infection to impart long-term enhanced immunity against re-infection. We are currently dedicated to elucidating the developmental cues that govern the commitment of brain infiltrating CD8 T-cell to resident memory T- cells. Being resident innate immune cells, microglia provide the first line of defense against CNS insult and acute inflammation. Using experimental in vivo models, our work has shown that brain-resident microglial cells are activated by infiltrating cells from the peripheral immune system. Resting microglia (CD11b(+)CD45(int)) from uninfected brain express very low constitutive levels of MHC class II (<5%). However, following murine cytomegalovirus (MCMV) or herpes simplex virus (HSV)-1 brain infection, MHC class II expression is strikingly upregulated on approximately 90% of these cells, including in widespread areas distal to viral infection. This activation within the CNS is not seen following MCMV-infection of IFN-γ-knockout animals, yet it can be restored following reconstitution with IFN-γ-producing CD8(+) T lymphocytes. Importantly, these neuroimmune responses persist in the absence of active viral replication and the resident microglia remain chronically activated (>90 days podt infection). These findings demonstrated that resident brain cells react to peripheral immune responses generated during viral infection, not simply to the viral proteins themselves. By understanding the role of microglia in modulating the brain infiltrating CD8 T-cells, we can learn how to manipulate the immune response within the brain for eradication of persistent infection. We are optimistic that our research efforts will provide critical insights into the neuroimmunopathogenic mechanisms responsible for chronic viral infections and, more importantly, translate into development of more effective therapies.

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