Wednesday, April 2, 2025
4/2/2025
The Role of Interferon Lambda in Alpha Herpesvirus Neuroinvasion - The Role of Interferon Lambda in Alpha Herpesvirus Neuroinvasion Project Summary: Virus infections typically begin in peripheral tissues and usually do not spread to the nervous system (NS) because it often represents a dead end for both the host and the pathogen. However, some viruses, such as alpha herpesviruses (e.g., Herpes Simplex Virus-1, HSV-1), have evolved mechanisms to efficiently enter the peripheral nervous system (PNS) and spread between connected neurons after replicating in mucosal epithelia. Although much is known about productive infection in epithelial cells and some details of the latency phase in neurons, the molecular events of viral invasion from epithelial cells to the nervous system and the responses of peripheral axons to this process are not well understood. This proposal focuses on the initial steps of alpha herpesvirus invasion of the PNS. We hypothesize that the response of peripheral nerves to cytokines, particularly interferon lambda (IFN-λ) produced by infected epithelial cells, affects the transport of viral particles in axons and ultimately determines the establishment of infection (quiescent or productive) in the neuronal nucleus, impacting the frequency of reactivations. Preliminary data suggest that axons of peripheral neurons respond to IFNs produced in infected epithelia, resulting in a non-canonical antiviral state specifically targeting alpha herpesvirus transport. Using this foundation, we have developed an in vitro latency model by infecting isolated axons with low multiplicity of pseudorabies virus (PRV) and HSV-1. This proposal aims to elucidate the mechanisms of local axonal responses to IFN-λ and their effects on viral invasion of the nervous system. Additionally, it seeks to determine how these initial virus-host interactions influence the mode of infection (latent vs. productive) in neurons and whether peripheral IFN-λ responses dictate the efficiency of infection establishment. Our primary hypotheses are: i) axons serve as front-line sensors and responders to viral infection and inflammation, ii) IFN-λ responses in axons affect alpha herpesvirus particle transport, the establishment of lifelong infection in neuronal nuclei, and viral spread within the nervous system. To test these hypotheses, we will leverage state-of-the-art technologies we developed during my previous studies, including: i) tri-chamber Campenot chambers that physically isolate axons from neuronal cell bodies, ii) live-cell optical imaging to track entry and subsequent axonal transport of individual virus particles in the presence or absence of cytokines, inhibitors, or injury, iii) identification of nascent RNA and proteins in neurons, iv) an in vitro latency model to study the early events in latency establishment. By understanding the immediate and local responses of PNS axons to incoming virus particles and inflammatory cytokines before new viral gene products are made, this research will provide deeper insights into how the nervous system is protected from infection. It will also reveal novel aspects of the molecular basis for latency, potentially leading to new therapeutic strategies against alpha herpesvirus infections.
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