An Age-Dependent Role of the Inflammasome in the Pathogenesis of HSV Encephalitis

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Project Summary Herpes simplex virus (HSV) infection in adults is often subclinical, but infection in neonates commonly leads to severe morbidity and mortality from disseminated disease or encephalitis. By contrast, HSV encephalitis (HSE) is rare in adults with an incidence of 1 in 1,000,000. The precise reason for this difference in susceptibility and outcomes is unknown, but differences in the immune responses in the neonatal brain and the adult brain have been implicated. Although numerous studies have focused on innate immune factors that restrict viral replication, few have examined the pro-inflammatory pathways that may be detrimental during infection. The inflammasome is a multi-protein signaling platform that leads to the processing and release of the pro- inflammatory cytokine interleukin-1β (IL-1β). Upon stimulation of an inflammasome pattern recognition receptor, the inflammasome complex oligomerizes and activates pro-caspase-1, allowing for the cleavage of IL-1β. The best characterized inflammasome is the NLRP3 inflammasome due to its wide range of activating stimuli, but several other inflammasomes have been characterized and are known to be activated by HSV in vitro. Several other viral infections are known to be worsened by the inflammation generated by the NLRP3 inflammasome. My preliminary data suggests that one or more inflammasome complexes contribute to mortality in a murine model of HSE. I hypothesize that the inflammation generated by the inflammasome contributes to the pathogenesis of herpes simplex encephalitis. A deficiency in type I interferon (IFN) signaling in the neonatal brain likely contributes to increased susceptibility to HSV infection. Importantly, the type I interferon pathway acts as a negative regulator of IL-1β production and inflammasome activation to prevent dangerous levels of inflammation. The decreased capacity for type I IFN signaling in the neonate suggests a lack of negative regulation of the inflammasome during HSV infection. Accordingly, my preliminary data suggests that IL-1β is upregulated to a greater degree in the neonate during infection than in the adult. Therefore, I also hypothesize that a deficiency in Type I IFN signaling in the neonate contributes to differences in inflammasome activation between neonates and adults during HSV encephalitis. Using a murine model of HSE with mice genetically deleted for inflammasome components, I will elucidate the specific inflammasomes that contribute to pathogenesis. I will characterize the resulting cytokine profile and immune cell infiltrate that are generated downstream of the inflammasome during infection. Finally, I will determine the extent to which inflammasome activation is regulated by the type I IFN system using IFN-receptor knockout mice. These experiments will advance our understanding of the pathogenesis of HSV encephalitis and the factors that contribute to more severe disease in neonates.