Neuronal Consequences of UL12.5-Induced Innate Immune Sensing That Drive HSV-1 Escape from Latency 20 views

Herpes Simplex Virus type 1 (HSV-1) is a neurotropic virus that has evolved in close coordination with neuronal signaling pathways. While HSV-1 undergoes productive lytic replication in mucosal epithelial cells during acute infection, the virus establishes lifelong latency in peripheral sensory neurons, from which it can periodically reactivate to cause recurrent disease. The cellular mechanisms governing latency and reactivation reflect the profound dependence of HSV-1 on neuron-specific signaling pathways. While previous work has defined critical steps in HSV-1 reactivation, including activation of the dual leucine zipper kinase (DLK) and c-Jun N-terminal kinase (JNK) stress pathways, the viral and host factors that initiate the earliest transcriptional events during exit from latency remain understudied. Using an in vitro model of latency and reactivation in primary peripheral neurons, I investigated the role of viral protein function and neuronal innate immune signaling pathways in the context of HSV-1 reactivation. The overall focus of this dissertation sought to define the viral and cellular components that support the transition from a transcriptionally silent latent infection to productive reactivation. Together with Sean, Matthew, and others, we identified UL12.5 as the first viral protein required for HSV-1 reactivation, functioning specifically during Phase I—the earliest stage of reactivation, previously thought to proceed entirely through host machinery. UL12.5 localizes to mitochondria where it depletes mitochondrial DNA and RNA, triggering activation of cytosolic nucleic acid sensing pathways including STING pathway. Strikingly, I found that this innate immune activation in neurons does not induce a canonical type I interferon response. Instead, neurons route these danger signals through non-canonical NF-κB signaling mediated by IKKα and RelB—a neuron-specific adaptation that HSV-1 exploits to promote its own reactivation. Loss of either STING and MAVS signaling, or disruption of non-canonical NF-κB pathway and its components IKKα or RelB, significantly impairs Phase I lytic gene expression and blocks progression to full productive reactivation. These observations reveal that HSV-1 has evolved to co-opt neuronal innate immune pathways, converting what would typically be an antiviral defense mechanism into a pro-reactivation signal that facilitates viral gene expression from the chromatinized latent genome. Together, these findings fundamentally revise our understanding of HSV-1 reactivation by identifying UL12.5 as a viral trigger that initiates exit from latency through activation of neuron-specific innate immune signaling. My work reveals that neurons respond to intracellular danger signals through distinct pathways compared to other cell types, and that HSV-1 has evolved to exploit these neuron-specific features to support reactivation. These discoveries provide insight into the molecular events that govern the earliest stages of viral reactivation and identify multiple potential therapeutic targets—including UL12.5 expression and activity, mitochondrial nucleic acid sensing pathways, and non-canonical NF-κB signaling—that could be leveraged to prevent HSV-1 reactivation and reduce the burden of recurrent herpetic disease.

PHD (Doctor of Philosophy)

HSV-1; Virology; Immunology; Innate Immunity; DNA virus; Neurobiology; Neurotropic virus; Mitochondria; UL12.5; HSV-1 Reactivation; Non-canonical NF-kB; IKKα; RelB

English

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2026-04-21