Friday, April 26, 2024
4/26/2024
Project Summary & Abstract Herpes simplex virus 1 (HSV-1), an important human pathogen, establishes life-long latency in neurons within trigeminal ganglia (TG) and CNS, including brainstem. External stressors periodically trigger reactivation from latency, resulting in recurrent ocular disease and encephalitis. The synthetic corticosteroid dexamethasone significantly enhances reactivation from latency in HSV-1 latently infected mice. Conversely, a glucocorticoid receptor (GR) antagonist significantly reduces reactivation from latency. A transcription factor activated by the Wnt pathway, b-catenin, is expressed in more TG neurons during latency relative to stress induced reactivation suggesting b-catenin maintains latency. GR and a stress induced transcription factor, Krüppel like transcription factor 15 (KLF15), form a feed forward loop that synergistically transactivates viral immediate early promoters required for productive infection. Based on these exciting unpublished studies, we hypothesize that stress, via GR activation, has multi-pronged effects on the latency-reactivation cycle. An important early step during reactivation is a stressful stimulus disrupts latency by suppressing the canonical Wnt/b- catenin signaling pathway. A second early step is GR and KLF15 cooperatively stimulate viral gene expression, ultimately leading to virus production. Studies in this proposal will directly test this hypothesis. For Aim 1, HSV-1 reactivation from latency will be compared in mice that do not express GR in TG or KLF15 knockout mice relative to wild-type mice. For Aim 2, we will investigate how GR and KLF15 synergistically activate viral transcription. Finally, differentially expressed genes associated with the Wnt/b-catenin signaling pathway will be identified during latency and reactivation from latency (Aim 3). Completion of these studies will reveal how stress disrupts latency and directly stimulates viral gene expression. !
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