Neuronal innate immune signaling supports herpes virus reactivation

As a neurotropic virus, herpes simplex virus-1 (HSV) has evolved in close coordination with neuronal signaling pathways. While HSV can undergo productive lytic replication in mucosal epithelial cells and peripheral neurons during acute infection, the virus can only establish latency and undergo reactivation from peripheral neurons. The cellular mechanisms governing latency and reactivation reflect the dependence of HSV on neuronal signaling pathways. While our lab and others have defined critical steps in HSV reactivation, such as dual leucine zipper kinase (DLK) and c-Jun N-terminal kinase (JNK) activation, additional signaling mechanisms have yet to be elucidated. Using a combination of in vivo studies and an in vitro model of latency in primary peripheral neurons, we investigated the role of the innate immune signaling pathways in the context of HSV reactivation. The overall focus of this dissertation sought to define components of the neuronal innate immune system that support the transition from a transcriptionally silent latent infection to reactivation and the production of infectious virus. We found that HSV uses innate immune signaling to both trigger reactivation as well as activate pathways required to facilitate lytic gene transcription early in reactivation. After determining that neuronal hyperexcitability is a trigger of HSV reactivation, we found that the inflammatory cytokine interleukin 1β (IL-1β) induces DLK-dependent reactivation by prompting a hyperexcitable state in mature neurons. Additionally, we identified a role for the HSV protein UL12.5 in promoting lytic gene expression during reactivation by activating stimulator of interferon genes (STING), which regulates innate immunity downstream of DNA-sensing by cyclic GMP-AMP synthase (cGAS). UL12.5 is the first viral protein known to exclusively support HSV reactivation and, importantly, to be required for lytic gene expression in Phase I. Our data also suggests that UL12.5 has the potential to activate RNA-sensing pathways in addition to the cGAS-STING DNA-sensing pathway. Together, these observations demonstrate the ability of HSV to co-opt neuronal immune pathways to support HSV reactivation and provide insight into the signaling events that mediate early events in reactivation.