The Role of the Host Response and Viral Genetic Variation in the Pathogenesis of Herpes Simplex Encephalitis

Hayes, Cooper Kincaid

doi:https://doi.org/10.21985/n2-6p91-pc48

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The Role of the Host Response and Viral Genetic Variation in the Pathogenesis of Herpes Simplex Encephalitis

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Herpes simplex virus (HSV) encephalitis (HSE) is the most common cause of sporadic fatal encephalitis, and despite targeted antiviral therapy, outcomes remain poor. While rare in adults, neonates are significantly more susceptible to severe HSV disease. Understanding both the host and viral factors that contribute to pathogenesis is critical to improving outcomes in this devastating illness. Although the innate immune system is critical for restricting HSV-1 replication in the brain, a careful balance must be struck between effective antiviral control and excessive neuroinflammation. In Chapter III, I investigated the contribution of inflammasomes to pathogenesis in a murine model of HSE. Inflammasomes are signaling platforms that initiate a proinflammatory response by activating the cytokines IL-1β and IL-18. I found that mice deficient in the inflammasome adaptor protein, ASC, had significantly improved survival and lower levels of IL-1β and IL-18 in the brain during infection. Importantly, this difference in survival was independent of viral replication in the central nervous system. I identified microglia, the resident macrophages of the CNS, as the essential mediators of this response. These results suggest a promising new target in combating harmful inflammation in HSE.In Chapter IV, I used single-nucleus RNA sequencing of brain tissue from adult and neonatal mice infected with HSV-1 to identify host factors that contribute to age-dependent susceptibility to infection. The neonatal brain was overwhelmingly more susceptible to infection without an age-dependent tropism towards a particular cell type. Surprisingly, I found that transcriptional levels of antiviral genes were similar between neonates and adults at baseline. Instead, I found that the long noncoding RNA Meg3 is expressed at higher levels in the neonatal brain and inhibits host cell apoptosis during HSV-1 infection. Our study highlights a potential role for the developmental state of a cell to influence viral susceptibility outside of traditional antiviral gene expression. Finally, in Chapter V I investigated the contribution of viral variation to HSE pathogenesis. As a DNA virus, HSV is traditionally thought of as relatively invariant and previous studies have focused on host genetic factors to explain varied clinical courses in neonates. I evaluated clinical HSV-2 isolates from neonates with different neurologic outcomes in several models of HSV infection. I found that isolates taken from neonates with encephalitis are more neurovirulent in human neuronal culture and mouse models of HSV encephalitis, as compared to isolates collected from neonates with mild peripheral disease. These findings suggest that inherent characteristics of the infecting HSV strain contribute to disease outcome following neonatal infection.

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