Leukocyte Recruitment into the CNS is Mediated via Microglia-Dependent Signaling Following Neurotropic Herpesvirus Infection
Webb, Connor M.
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Neurotropic viruses are diverse and can establish lifelong and lethal infections in the brain, inducing encephalitis and contributing to severe neurodegeneration. However, the mechanisms through which microglia, the brain's main immunocompetent cells, recognize and control viral infection and inflammation have remained unclear. Using a pseudorabies virus derivative as an alphaherpesvirus model, we induced a specific transsynaptic infection into the neurons of the brain to view the microglial response. With a selective elimination of microglia using a CSF1R antagonist, combined with immunofluorescent confocal microscopy and flow cytometric analysis, we found that viral load was worsened in the absence of microglia. Additionally, leukocyte infiltration into the CNS was absent in microglia deficient mice. We identify microglia as necessary mediators of leukocyte recruitment into the brain despite blood-borne leukocyte populations remaining largely intact. Introducing our virus to primary isolated microglia cultures increased the production ofCCL2 and CCL5, suggesting these as potential cytokine signals used to recruit leukocytes into the infected brain. Finally, we determined by measuring IgG infiltration into the brain and ICAM expression in the vasculature that microglia do not alter the integrity of the blood-brain barrier in the current model, suggesting the involvement of additional modulators of BBB permeability. By revealing the importance of microglial recruitment and phagocytosis of viral-infected neurons, along with their essential role in neuroinflammation, we are closer to developing targeted therapies to control neurotropic virus infections and the neurodegeneration that it induces. The contribution of neuroinflammation to a wide range of neurodegenerative diseases suggests these findings could have implications beyond neurotropic virus infection.