The Role of Innate Immunity and Interferon-Inducible Genes in the Regulation of Host Defense in Re-Emerging West Nile Virus and Influenza

In these studies, we showed that CXCL-10, an interferon-inducible chemokine, is highly expressed early following infection with Influenza and West Nile Virus. CXCL-10 can induce lymphocyte apoptosis by sustained activation of p38 MAPK. This study showed that p38 MAPK is the kinase that inactivates antiapoptotic Bcl-2 proteins by phosphorylation, activation of executer caspases, and initiation of programmed cell death in response to CXCR-3 ligation in T cells. The high expression of CXCL-10 induced by viral infection may contribute to the T cell depletion noted during the pathogenesis of severe remerging viral infections and play a role in antiviral defense. Alternatively, CXCL-10 may contribute to the prompting of apoptosis in other subsets of T lymphocytes, including those lymphocytes that were transiently activated but later lacked the appropriate sets of specific co-stimulating signals required to ensure their survival.;We studied CXCL-14 function in viral and bacterial infection by generating CXCL-14 knockout mice (CXCL-14KO). Other than decreased body weight, the CXCL-14KO mice exhibited no noticeable phenotype. Macroscopic and microscopic analysis revealed no gross or obvious morphological abnormalities. We showed that in mice, CXCL-14 does not seem to be indispensable for blood cell homeostasis and protective immune responses against Influenza virus or E. coli infection.;In conclusion, CXCL-10 induced apoptosis may contribute to innate antiviral defense. Down regulation of TLRs and their function due to aging may have consequences for innate immunity to WNV. Finally, the role of CXCL-14 in antiviral defense is uncertain but likely serves a redundant function.;We studied WNV infection as a serious disease of old age. We studied the molecular and immunological foundation of the age-related decline in innate immunity and increase in vulnerability to WNV. We observed a qualitative and quantitative defect in TLRs expression and function in advanced age, which likely leads to augmented vulnerability to neurological WNV infections. Furthermore, we reported for the first time that aged WNV patients who express higher levels of proinflammatory cytokines exhibited fewer symptoms. Moreover, we also showed that high expression of CXCL-10 is associated with symptomatic WNV disease and CXCL-9 with asymptomatic and may be good prognosis of WNV disease.