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 further characterize how IPS-1 modulates the inflammatory response to WNV infection, we measured levels of systemic type I IFN, proinflammatory cytokines, and chemokines present in the serum of WNV-infected mice at 1 and 4 days pi. Paradoxically, a trend towards more rapid induction and increased levels of type I IFN were observed in the serum of IPS-1 2/2 mice compared to wild type mice (Fig 5A) . We note that in this case type I IFN was detected and quantified through a mouse-specific type I IFN bioassay, which does not differentiate between the IFN-a or -b species. This result is consistent with our recent studies showing that serum type I IFN levels accumulate during WNV infection in an IRF-7-dependent but IRF-3-independent manner [8, 9] . In this case IFN-a species are likely accumulating through a TLR7dependent signaling pathway involving plasmacytoid DCs, which do not require the RLR pathway for IFN production [38] . More recently, Town et al. assessed the role of TLR7 and MyD88 2/2 during WNV infection and found that mice lacking MyD88 produced elevated levels of systemic IFN during WNV infection [25] . Thus, during WNV infection systemic IFN is regulated through RLR-dependent and independent processes. Correspondingly, when compared to wild type mice, IPS-1 2/2 infected animals, which show higher viremia (Fig 1B) produced increased serum levels of proinflammatory cytokines and chemokines in response to WNV infection. Elevated levels of systemic IL-6, TNFa, CXCL10, and IFN-c were observed at 1 and/or 4 days pi in IPS-1 2/2 mice (Fig 5B) . Serum cytokine levels were also compared between uninfected wild type and IPS-1 2/2 mice and showed no differences in basal cytokine expression (data not shown). These results demonstrate that in the absence of IPS-1, greater proinflammatory cytokine and chemokine responses are induced during WNV infection.