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

(2) While the quantity of virus-specific IgM and IgG antibody responses were greatly enhanced in the absence of IPS-1, there was a marked reduction in antibody quality in terms of neutralization capacity. In contrast deficiencies in TLR3 or MyD88 (data not shown) did not alter virus-specific antibody responses and neutralization capacities. Collectively, these findings suggest that RLR-dependent signaling coordinates effective antibody responses during WNV infection through as yet undefined pathway. (3) While systemic IFN responses provide a link between innate and adaptive immune responses, our studies suggest that the PRR signaling pathways (RLR-dependent vsindependent) and levels of IFN production in combination with production other proinflammatory cytokines or chemokines regulate the quantity and quality of the immune response during virus infection. Thus, in the absence of IPS-1 signaling, infected conventional DCs or Mw, two integral cell types in establishing adaptive immunity, likely do not produce IFN or the normal array and level of proinflammatory cytokines/ chemokines. Instead, IFN and other mediators may be strictly produced by infected or bystander cells during WNV infection, occurring with altered kinetics and magnitude, through TLR-dependent pathways, such as TLR3 and/or TLR7 [23, 25] . (4) In the absence of IPS-1, the enhanced expansion of Ly6C+ ''inflammatory'' DCs failed to limit early WNV replication and dissemination. This inflammatory DC subset migrates to sites of infection, secretes pro-inflammatory cytokines, and promotes CD8+ T cell expansion during a secondary virus infection, suggesting it sustains the effector T cell response [59] . Our data indicate that Ly6C+ DC recruitment and/or expansion is governed by IPS-1-dependent events of RLR signaling. Thus, the aberrant recruitment/expansion of these inflammatory DCs may contribute to immunopathogenesis and limit development of an effective immune response to control WNV virus infection. (5) The lack of T reg expansion during WNV infection correlated with altered IFN levels, increased proinflammatory cytokines and chemokine levels, and an increased number and distribution of antigen-specific CD8+ T cells. These observations implicate an indirect or direct role for IPS-1 in regulating T reg levels during WNV infection, and provide evidence that links a lack of T reg expansion to immune dysregulation.