IL-1β Signaling Promotes CNS-Intrinsic Immune Control of West Nile Virus Infection

West Nile virus (WNV) is an emerging flavivirus capable of infecting the central nervous system (CNS) and mediating neuronal cell death and tissue destruction. The processes that promote inflammation and encephalitis within the CNS are important for control of WNV disease but, how inflammatory signaling pathways operate to control CNS infection is not defined. Here, we identify IL-1 beta signaling and the NLRP3 inflammasome as key host restriction factors involved in viral control and CNS disease associated with WNV infection. Individuals presenting with acute WNV infection displayed elevated levels of IL-1 beta in their plasma over the course of infection, suggesting a role for IL-1 beta in WNV immunity. Indeed, we found that in a mouse model of infection, WNV induced the acute production of IL-1 beta in vivo, and that animals lacking the IL-1 receptor or components involved in inflammasome signaling complex exhibited increased susceptibility to WNV pathogenesis. This outcome associated with increased accumulation of virus within the CNS but not peripheral tissues and was further associated with altered kinetics and magnitude of inflammation, reduced quality of the effector CD8(+) T cell response and reduced anti-viral activity within the CNS. Importantly, we found that WNV infection triggers production of IL-1 beta from cortical neurons. Furthermore, we found that IL-1 beta signaling synergizes with type I IFN to suppress WNV replication in neurons, thus implicating antiviral activity of IL-1 beta within neurons and control of virus replication within the CNS. Our studies thus define the NLRP3 inflammasome pathway and IL-1 beta signaling as key features controlling WNV infection and immunity in the CNS, and reveal a novel role for IL-1 beta in antiviral action that restricts virus replication in neurons.