Microglia promote bystander activated T cell-mediated neurological disease during viral infection 3059

Abstract Description Many viral infections have been linked to the development of debilitating neurological disorders. However, the mechanism governing virus-induced neuropathology remains poorly understood, particularly when the virus is not directly neuropathic. Using a mouse model of Zika virus (ZIKV) infection, we find that brain ZIKV titers do not correlate with the severity of neurological disease. Instead, ZIKV-infected brains exhibit microglial activation and infiltration of ‘bystander activated’ CD8+ T cells expressing the NK cell receptor, NKG2D. To assess the role of these T cells in virus-induced neuropathology, we treated ZIKV-infected mice with antibodies to deplete CD8+ T cells or block NKG2D signaling. Both treatments completely prevented against the development of paralysis without altering the viral load in the serum or brain, suggesting that bystander activated T cells mediate virus-induced neurological disease. Interestingly, depletion of brain-resident microglia using the drug PLX3397 also prevented development of neurological disease. However, microglia depletion did not reduce bystander activated T cell numbers in the brain, suggesting that microglia influence bystander T cell function rather than recruitment. Overall, we have identified a novel mechanism where microglia promote bystander activation and function of CD8+ T cells neurological disease. Our findings reveal several strategies for further investigation of treatments for virus-induced neurological diseases. Funding Sources Canadian Institutes for Health Research Topic Categories Viral Immunology (VIR)