Contribution of IFNg, NK and T cells to the immune pathology of West Nile virus encephalitis

Abstract

West Nile virus (WNV) is a mosquito-borne, neurotropic virus that can cause lethal encephalitis. Pathology in West Nile virus encephalitis is mediated by infiltration of leukocytes, in particular bone marrow-derived, nitric oxide-producing Ly6Chi inflammatory monocytes. In this project, we investigated factors associated with mobilization of monocytes from the bone marrow and infiltration of these cells into the brain to reveal potential early targets for treatment. NK cells are considered unimportant in WNV encephalitis as infection up-regulates cellular expression of MHC I, which inhibits NK cell lysis; nonetheless, they constitute 10% of the leukocytes infiltrating into the WNV-infected brain, making them the second largest infiltrating population after monocytes. Detailed analysis of NK cell phenotype and function revealed that, while NK cells seem inhibited in the brain, they are the main IFN producing cells in the bone marrow. Depletion of IFN or NK cells themselves resulted in an increase in the number of Ly6Chi monocytes in the bone marrow, suggesting a role for NK cell derived IFN in inflammatory monocyte egress from the bone marrow. To explore the role of NK cells and IFN in WNV infection further we investigated disease in SJL/J mice, which have reduced NK cell and IFNγ responses. CNS infiltration of NK cells and inflammatory monocytes was substantially reduced in WNV-infected SJL/J mice, compared to C57BL/6 mice. However, disease in SJL/J mice was more severe and virus titres in the brain were higher. Intriguingly, infiltration of T cells and pDC was increased in the brain of WNV-infected SJL/J mice, raising the possibility that these cells contribute to disease severity. Further study of the role of T cells in WNV encephalitis revealed that CD4+ T cells play a pivotal role in viral clearance as CD4+ T cell depleted animals have reduced survival and higher viral loads in the brain. In contrast, depletion of CD8+ T cells seemed to improve disease signs, suggesting these cells caused damage to the brain. Our data suggest that in WNV encephalitis, NK cells in the bone marrow drive IFNγ-mediated priming and egress of pathogenic inflammatory monocytes. These findings lay the groundwork for the development of potential early treatment targets for WNV encephalitis