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

Altered WNV-specific antibody profiles in IPS-1 2/2 mice WNV-specific antibody responses are essential for suppressing viremia and virus dissemination and limiting lethal WNV infection [39, 40] . To determine if a deficiency in IPS-1 modulated the quality and quantity of the humoral immune response, we characterized the antibody profile in sera during WNV infection. In wild type mice, neutralizing virus-specific IgM antibodies are typically detectable by day 4 pi with WNV and production of neutralizing virus-specific IgG antibodies follow between days 6 and 8 pi [40] . A time course analysis in wild type and IPS-1 2/2 infected mice showed that between 4 and 6 days pi, WNV-infected IPS-1 2/2 mice exhibited significantly higher levels of virus-specific IgM, IgG, and IgG subclasses as compared to infected wild type mice ( Table 1) . WNV-specific IgG1 antibodies were detected at low levels on day 6 pi in sera from wild type and IPS-1 2/2 mice. Additionally, we observed a ,72.9-fold increase in WNV-specific IgG2a levels in infected IPS-1 2/2 as compared to wild type mice on day 6 pi and ,2.2-fold increase on day 8 pi. Assessment of the virus-specific antibody responses through a PRNT assay revealed that neutralization titers in sera from wild type mice increased dramatically between 6 and 8 days pi. Sera from IPS-1 2/2 infected mice exhibited a modest increase in neutralization titer to 1:1280, despite having much higher levels of virusspecific antibodies. This difference translated into a serum neutralization index that was ,39-fold lower on day 6 pi in the infected IPS-1 2/2 mice compared to wild type mice. These results demonstrate that the humoral responses in WNV-infected IPS-1 2/2 mice are distinct from responses in wild type infected mice. Thus, RLR signaling and IPS-1 actions likely contribute to regulatory processes that govern the levels, IgG class switching, and neutralizing capacity of antibodies generated in response to WNV infection.