IPS-1 Is Essential for the Control of West Nile Virus Infection and Immunity

Suthar, Mehul S.; Ma, Daphne Y.; Thomas, Sunil; Lund, Jennifer M.; Zhang, Nu; Daffis, Stephane; Rudensky, Alexander Y.; Bevan, Michael J.; Clark, Edward A.; Kaja, Murali-Krishna; Diamond, Michael S.; Gale, Michael

To evaluate the composition and antigen-specificity of the inflammatory cells within the brains of WNV-infected mice, lymphocytes were isolated from infected brains on day 6 pi and were characterized from pools (n = 5) of wild type and IPS-1 2/2 infected mice. Brains from IPS-1 2/2 infected mice showed an 2.9fold increase in the total number of immune cells as compared to wild type infected mice (Fig 4B) , and this was associated with an increase in absolute numbers of infiltrating CD4+ and CD8+ T cells ( Fig 4C) . Among the brain CD8+ T cells isolated from IPS-1 2/2 mice, there was a remarkable 27-fold increase in the number of antigen-specific cells that expressed IFN-c after treatment with an immundominant NS4B peptide ( Fig 4D) [35, 36] . Analysis of microglia/Mw cells, based on relative surface expression of CD45 and CD11b [37] , revealed increased numbers of microglial cells (CD45+ lo /CD11b+) and infiltrating macrophages (CD45+ hi / CD11b+) within the brains of infected IPS-1 2/2 mice when compared to wild type mice (Fig 4E) . Similar findings were observed in the spinal cords from infected IPS-1 2/2 mice (data not shown). Combined with the histological analysis, these results demonstrate that in the absence of IPS-1, WNV infection induces a strong inflammatory response in the CNS. While this response is likely associated with increased viral loads, the failure of this increased inflammatory response to elicit protection or control CNS pathology, in the absence of IPS-1, suggests a role for the RLR signaling pathway as a regulatory program that controls the quality of the inflammatory response to WNV infection.