Asc-Dependent Inflammasomes Contribute To Immunopathology And Mortality In Herpes Simplex Encephalitis

Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis, and despite targeted antiviral therapy, outcomes remain poor. Although the innate immune system is critical for restricting herpes simplex virus type I (HSV-1) in the brain, there is evidence that prolonged neuroinflammation contributes to HSE pathogenesis. In this study, we investigated the contribution of inflammasomes to disease pathogenesis in a murine model of HSE. Inflammasomes are signaling platforms that activate the pro-inflammatory cytokines interleukin-1 beta (IL-1 beta) and IL-18. We found that mice deficient in the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), had significantly improved survival and lower levels of IL-1 beta and IL-18 in the brain. Importantly, this difference in survival was independent of viral replication in the central nervous system (CNS). We found that microglia, the resident macrophages of the CNS, are the primary mediators of the ASC-dependent inflammasome response during infection. Using in vitro glial infections and a murine HSE model, we demonstrate that inflammasome activation contributes to the expression of chemokine (C-C motif) ligand 6 (CCL6), a leukocyte chemoattractant. The lower concentration of CCL6 in the brains of ASC(-/-) mice correlated with lower numbers of infiltrating macrophages during infection. Together, these data suggest that inflammasomes contribute to pathogenic inflammation in HSE and provide a mechanistic link between glial inflammasome activation and leukocyte infiltration. The contribution of inflammasomes to survival was independent of viral replication in our study, suggesting a promising new target in combating harmful inflammation in HSE.Author summaryAlthough the immune system is critical for controlling herpes simplex virus (HSV) infection in the central nervous system (CNS), a prolonged or excessive immune response may be harmful. We studied the contribution of inflammasomes, innate immune proteins that initiate a pro-inflammatory response, to detrimental neuroinflammation in a murine model of herpes simplex encephalitis (HSE). We found that inflammasomes that rely on the adaptor protein ASC contribute to mortality and neuroinflammation independent of controlling viral replication. Additionally, we demonstrate that the inflammasome response to HSV is primarily mediated by microglia and leads to an influx of macrophages in the CNS. These results provide insights into the mechanisms that drive pathogenic inflammation in HSE and suggest a promising therapeutic target in treating HSE.