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

While their importance in autoimmunity is established [60] , recent studies have implicated an integral role for T regs in controlling inflammation and adaptive immune responses during acute virus infections [26, 43, 44] . During acute infection T regs function to locally contain and control the immune response with the dual outcome of suppressing viral dissemination while decreasing the likelihood of immune-mediated pathology. In support of this model, infection studies with herpes simplex virus (HSV) and mouse hepatitis virus (MHV), two well established models of viral encephalitis, have demonstrated the importance of T regs in limiting proinflammatory cytokine and chemokine responses to protect the CNS and enhance survival [26, 43] . Recent work also implicates T regs in the control of WNV pathogenesis, wherein peripheral expansion of T regs was associated with asymptomatic infection among WNV-infected blood donors but reduced T reg levels associated with WNV disease [45] . Furthermore, these studies revealed that the conditional depletion of T reg cells in mice results in enhancement of WNV virulence and expansion of antigen-specific CD8 T cells. Interestingly, from our studies, type I IFN does not appear to be the major contributor to T reg expansion during WNV infection, as T regs failed to expand in the IPS-1 2/2 infected mice despite their elevated levels of systemic type IFN. These observations suggest that RLR signaling through IPS-1 provides essential signals that directly or indirectly impart the expansion of T regs during WNV infection.