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

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Abstract
The innate immune response is essential for controlling West Nile virus (WNV) infection but how this response is propagated and regulates adaptive immunity in vivo are not defined. Herein, we show that IPS-1, the central adaptor protein to RIG-I-like receptor (RLR) signaling, is essential for triggering of innate immunity and for effective development and regulation of adaptive immunity against pathogenic WNV. IPS-1−/− mice exhibited increased susceptibility to WNV infection marked by enhanced viral replication and dissemination with early viral entry into the CNS. Infection of cultured bone-marrow (BM) derived dendritic cells (DCs), macrophages (Macs), and primary cortical neurons showed that the IPS-1-dependent RLR signaling was essential for triggering IFN defenses and controlling virus replication in these key target cells of infection. Intriguingly, infected IPS-1−/− mice displayed uncontrolled inflammation that included elevated systemic type I IFN, proinflammatory cytokine and chemokine responses, increased numbers of inflammatory DCs, enhanced humoral responses marked by complete loss of virus neutralization activity, and increased numbers of virus-specific CD8+ T cells and non-specific immune cell proliferation in the periphery and in the CNS. This uncontrolled inflammatory response was associated with a lack of regulatory T cell expansion that normally occurs during acute WNV infection. Thus, the enhanced inflammatory response in the absence of IPS-1 was coupled with a failure to protect against WNV infection. Our data define an innate/adaptive immune interface mediated through IPS-1-dependent RLR signaling that regulates the quantity, quality, and balance of the immune response to WNV infection. West Nile virus (WNV) is a mosquito-transmitted RNA virus that has emerged in the Western hemisphere and is now the leading cause of arboviral encephalitis in the United States. However, the virus/host interface that controls WNV pathogenesis is not well understood. Previous studies have established that the innate immune response and interferon (IFN) defenses are essential for controlling virus replication and dissemination. In this study, we assessed the importance of the RIG-I like receptor (RLR) signaling pathway in WNV pathogenesis through analysis of mice lacking IPS-1, the central adaptor molecule of RLR signaling. Our studies revealed that IPS-1 is essential for protection against WNV infection and that it regulates processes that control virus replication and triggering of innate immune defenses. We found that IPS-1 plays an important role in establishing adaptive immunity through an innate/adaptive interface that elicits effective antibody responses and controls the expansion of regulatory T cells. Thus, RLRs are essential for pathogen recognition of WNV infection and their signaling programs help orchestrate immune response maturation, regulation of inflammation, and immune homeostasis that define the outcome of WNV infection.