Subdominant T-cell epitopes have previously been shown to mediate

Subdominant T-cell epitopes have previously been shown to mediate heterologous immunity in BAY 57-1293 the murine LCMV model, but immunodominant epitopes may also play a role. This has been suggested in studies of humans in whom immunodominant HLA-A2-restricted influenza M1-specific CD8+ T cells found to be cross-reactive to Epstein-Barr

virus BMLF-1 expand during acute infectious mononucleosis and are thought to contribute to lymphoproliferation 23. Similarly, in our model, CD8+ T cells specific for the immunodominant epitope are cross-reactive in both JEV and WNV-infected mice. In both JEV- and WNV-infected mice, higher frequencies of IFN-γ+ CD8+ T cells were Doxorubicin molecular weight detected compared

to frequencies of TNF-α+ CD8+ T cells on day 7 post-infection, as has been seen after acute LCMV infection, independent of stimulating peptide variant 24. However, we detected a significantly higher proportion of IFN-γ+TNF-α+ CD8+ T cells in mice infected with WNV compared with those immunized with both attenuated and pathogenic JEV strains (Fig. 2B–D), as well as higher TNF-α production on a per cell basis (Supporting Information Fig. 2). The role of TNF-α in WNV infection is pleiotropic and may lead to resolution of the infection or to immunopathology depending on the concentration of TNF-α. Wang et al. demonstrated decreased mortality from WNV infection in TLR3−/− mice, which they related to a decrease in TNF-α production and subsequent diminution in blood-brain

permeability resulting in reduced WNV neuroinvasion 25. However, Shrestha et al. demonstrated that neutralization of TNF-α in WNV-infected mice decreased their survival due to lower numbers of CD8+ T cells and macrophages trafficking to the brain 26. CD8+ T-cell production of TNF-α during acute WNV infection may contribute to their own trafficking into the central nervous system resulting in control of virus infection or increased immunopathology. The qualitative disparity in cytokine profiles during acute infection Reverse transcriptase with closely related viruses may be due to one of several factors: (i) differences in the kinetics of the response; (ii) differences in activation state in different virus infections; (iii) differences in viral burden and/or tissue tropism between attenuated JEV and WNV. To further delineate whether these differences are related to virus family versus viral virulence, we investigated responses to a pathogenic JEV virus strain, Beijing, at similar doses and clinical outcome to those of attenuated JEV SA14-14-2 and virulent WNV. At 1×103 pfu of JEV Beijing, no mortality was seen in 6- to 7-wk-old mice, which is similar to what was seen after the attenuated JEV SA14-14-2 at 1×106 pfu.

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