Encephalitis is a common and devastating consequence of infection with the fiavivirus West Nile virus (WNV), a rapidly emerging infectious disease. Although neurons are the primary target of central nervous system (CNS) infection, a hallmark of WNV encephalitis is the accumulation of inflammatory infiltrates extending from the meninges into the brain parenchyma that vary in severity between brain regions. This CNS inflammatory response is required for protection from lethal infection through the recruitment of leukocytes that clear virus through a variety of effector mechanisms. Some of these effects, however, may also be detrimental and contribute to the progression of neurologic disease. Thus, understanding the proinflammatory effects responsible for immune-mediated viral clearance during WNV infection of the CNS is an essential step for developing therapies that enhance clearance of virus in certain CNS compartments and limit inflammation in others. It is well established that inflammatory chemokines are upregulated in response to viral infections and that these molecules modulate the recruitment of leukocytes into infected tissues. In preliminary experiments, we have observed that the chemokine CXCL10 is highly upregulated in CNS tissues of mice with WNV encephalitis and localizes to subpopulations of neurons that are heavily infected with WNV. Moreover, neutralization of CXCL10 activity during WNV infection led to an increase in mortality, and treatment of neurons ex vivo with CXCL10 affects their survival. Based on these observations, the proposed research plans to directly test the role of CXCL10 in CD8+ T cell trafficking and neuronal injury in a well-defined mouse model of WNV encephalitis.
In Specific Aim 1 we will determine the regional and cellular sources of CXCL10 and its receptor, CXCR3, in the CNS of mice infected with WNV.
In Specific Aim 2, we will evaluate the effect of CXCL10 on different populations of neurons in vitro and on neuropathology in vivo after WNV infection.
In Specific Aim 3, using CXCL10 sufficient and deficient mice, we will determine the role of CXCL10 in coordinating the CD8+ T cell response against WNV in the different regions of the CNS. Overall, the goal of this proposal is to determine the mechanisms of neuronal protection and, possibly, injury induced by CXCL10 in WNV encephalitis. An enhanced understanding of the molecular signals that govern neuroinflammation and neuronal injury after infection will be critical to the development of targeted anti-inflammatory agents that mitigate the morbidity and mortality associated with WNV encephalitis.
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