Thursday, April 24, 2025
4/24/2025
Cross-talk of Neurons and HSV-1 during Viral Latency and Reactivation - Project summary and abstract During a malicious acute infection of epithelial cells, the HSV-1 completed a robust but well- organized gene expression (approximately 90 unique transcriptional units) in about 18-20 hours. The viruses then entered the ganglionic neurons through the innervating nerves and attempted to establish a dormant state of infection (latency). During the latency initiation, the vigorous viral gene expression is almost completely suppressed with only a few noncoding RNA detected in host neurons. We believe the neurons played a key role in the HSV-1 gene silencing and latency establishment. Previously, we used a rodent dorsal root ganglia (DRG) neuronal model to investigate the crosstalk between the viral replication and the neuronal discharge during latency and reactivation. We found that HSV-1 neuronal infection abolished the functional expression of voltage-gated Na+ and Ca2+ channels within hours. The neurons responded to the assault by rescuing the Na+ & Ca2+ channel expression during the course of latency and established latent reservoir. Induced viral reactivation would decrease the channel activity and increase viral gene expression. Elevated neuronal firing, nonetheless, would reduce the viral gene expression and release of infectious viruses. Therefore, we hypothesize that neuronal excitation offered an environment to suppress viral replication thus facilitate the establishment and maintenance of latency. To understand the mechanisms, we developed an in vitro human DRG neuronal model HD10.6, which mimics the mature neurons for latency and reactivation in human. We showed for the first time that a human microRNA overexpression facilitate a quiescent state of infection in HD10.6 without the need of replication inhibitor Acyclovir. In this proposal, we will first characterize the voltage-gated channel activity in HD10.6. Next, we will investigate how virus attacked the neuronal discharge to facilitate its infection. Finally, we will determine the counteracting schemes that neurons exploited to repress viral replication and keep the virus in a dormant state from reactivation.
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