Dissertation/Thesis Abstract

Pathogenesis and Control of Herpes Simplex Virus Infection in the Enteric Nervous System
by Khoury-Hanold, William, Ph.D., Yale University, 2016, 173; 10160864
Abstract (Summary)

Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) are among the most common human viral infections in the world. Together, they've established life-long infections in over four billion people making HSV-1 and HSV-2 not only extremely common viruses, but also extremely successful. This is due, in part, to their abilities to infect long-lived sensory neurons, prevent neuronal cell death following infection, evade immune clearance, establish a latent infection, periodically reactivate to produce progeny virus and infect the next naive host. While HSV-1 was typically transmitted via the oral route, it is now the leading cause of new genital herpes infections in Western nations. Despite its prevalence in the world, how HSV-1 spreads from the sensory nervous system to other peripheral nerve tissues is poorly understood. Furthermore, the overall pathogenesis of genital HSV- 1 infection remains unclear.

Using a mouse model of genital infection, I describe in Chapter 2 how HSV 1 and HSV-2 infection led to severe fecal and urinary retention, and that these signs correlated with lethality. While HSV-2 infection resulted in viral spread to the brain stem, we found no evidence of inflammation or infection in the brain following vaginal HSV-1 infection. Instead, we found that HSV-1 spread via the sensory neurons of the dorsal root ganglia (DRG) to the autonomic neurons of the enteric nervous system (ENS) in the large intestine. HSV-1 replication in the ENS led to neurodegeneration, which in turn resulted in the loss of peristalsis and the eventual development of toxic megacolon. Treatment with an osmotic laxative bypassed the need for a functioning ENS and therefore rescued mice from lethal infection. This suggests that lethality in this model is due to HSV-1 replication in the ENS and not the CNS. Overall, these results reveal an unexpected pathological consequence of HSV-1 spread beyond the sensory nervous system.

Infection of the DRG and ENS revealed a surprisingly dichotomous response, despite the fact that both are neuronal tissues responding to the same viral infection. In Chapter 3, I describe how RNA sequencing analysis revealed that HSV-1 infection of the DRG resulted in limited viral gene expression and restricted immune cell recruitment. In contrast, infection of the ENS led to robust viral gene transcription across the entire HSV-1 genome, pathological inflammatory responses, and neutrophil-mediated destruction of enteric neurons. Depleting neutrophils prevented enteric neurodegeneration and improved the overall survival of an otherwise lethal infection. These results highlight the importance of tissue-specific regulation of immunopathology behind the success of HSV as a persistent viral infection.

In Chapter 4, I describe our preliminary efforts to identify how sensory neurons restrict HST-1 gene transcription compared to enteric neurons, which seem less capable of doing so. We used a simple, in vitro system to investigate a host transcription factor, Runx1. In addition to its role in sensory neuron development, Runx1 may also bind the HST-1 genome and act as a transcriptional repressor at specific essential and nonessential HSV-1genes. This work seeks to expand our understanding of transcriptional control of HSV-1 and HSV 2 replication and how the developmental origins of the infected cell might provide the necessary transcription factors to promote or repress viral transcription.

Finally, in Chapter 5, I describe our efforts to elucidate how the host protein Pin1 affects HSV-2 pathogenesis following vaginal infection. As a peptidyl-prolyl cis/trans isomerase, Pin1 isomerizes scores of target proteins thereby regulating their activity at the post-translational level. Despite the known roles for Pin as a critical regulator of the interferon response and T cell activation, our results show that genetic deletion of Pin1 improved survival following lethal HSV-2 infection in an interferon- and T cell-independent manner. Instead, we noted decreased viral titers in the DRG and spine of Pin1-/- mice. Our preliminary data suggest that, in the absence of Pin1, neuronal retrograde transport is less efficient thus providing a rationale for decreased viral titers in the DRG and spine and increased rates of survival in Pin1-/- mice. Ongoing studies will clarify the role of Pin1 in HSV-infected neurons. Overall, this thesis contributes to our understanding of HSV neuronal spread, cell-type-specific and tissue-specific responses to infection, and viral pathogenesis. This work also provides insights into the design of future clinical studies to elucidate the potential viral causes of idiopathic gastrointestinal motility disorders.

Indexing (document details)
Advisor: Iwasaki, Akiko
Commitee:
School: Yale University
School Location: United States -- Connecticut
Source: DAI-B 78/01(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Physiology, Virology, Immunology
Keywords: Gastrointestinal Motility, Neurotropic Virus, Neutrophil-Mediated Immunopathology, Viral Infestion
Publication Number: 10160864
ISBN: 9781369157598
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