Mechanisms of CCR2-mediated neuroprotection in West Nile Virus infection

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DESCRIPTION (provided by applicant): ================== NOTICE: THIS ABSTRACT WAS EXTRACTED FROM APPLICATION AND HAS NOT BEEN PROOFED BY AN SRA.WHEN THERE ARE PROBLEMS WITH THE APPLICATION SCANNING PROCESS, THE EXTRACTED TEXT MAY BE INCORRECT OR INCOMPLETE. ================== Title: Mechanisms of CCR2-mediated neuroprotection in West Nile virus infection 1. Project Summary: West Nile virus (WNV) is a re-emerging mosquito-borne pathogen and the most common cause of epidemic viral meningo-encephalitis in the United States. Mortality due to WNV infection is high (~4% among symptomatic cases in the US epidemic), no specific treatments or vaccines for WNV are available, and knowledge of molecular pathogenesis is limited. Studies in a mouse model have suggested that monocytes in the CNS regulate clinical outcome during WNV encephalitis, but trafficking mechanisms have not been fully delineated. Previously, we and others showed that monocyte chemokine receptor CCR2 and three of its ligands, CCL2, CCL7, and CCL12, are induced in the CNS of WNV-infected mice. We have now obtained preliminary data indicating that mice genetically deficient in CCR2 have markedly increased mortality, and this was associated with markedly and selectively reduced monocyte accumulation in the CNS. Increased mortality was phenocopied in mice lacking CCL7, but not in mice lacking CCL2. Therefore, we hypothesize that the CCL7:CCR2 axis regulates neuroprotective inflammatory monocyte trafficking into the CNS during WNV infection. Mechanisms of CCR2- dependent monocyte trafficking in the context of disease must consider the known homeostatic role of CCR2 in the release of inflammatory monocytes from the bone marrow. Therefore, in Specific Aim 1, we will establish the role of CCR2 and its ligands in monocyte release from the bone marrow to the blood during WNV infection. In Specific Aim 2, we will determine the role of the CCL7:CCR2 axis in the regulation of monocyte recruitment from the blood into the inflamed CNS, and in neuroprotection during WNV encephalitis. Detailed knowledge of the precise molecular mechanisms controlling monocyte migration to the CNS will provide greater insight into innate immune control of WNV encephalitis and may provide the basis for novel immunomodulatory strategies to improve treatment outcomes in patients. West Nile virus (WNV) is transmitted by mosquitoes and causes annual outbreaks of encephalitis in the US. Since there are no specific therapies or vaccines, it is important to determine the molecular mechanisms involved in controlling the virus before and after it has entered the brain. A detailed understanding of these processes will not only provide new insight into how WNV causes disease but may provide new ways in which to interrupt the disease in infected people.