Author ORCID Identifier
Date of Award
2025
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
David A. Leib, PhD
Abstract
The ability of herpes simplex virus (HSV) to establish lifelong latency in sensory neurons makes it one of the most pervasive viruses worldwide. Although most HSV infections are asymptomatic or cause limited cutaneous symptoms, some give rise to serious central nervous system (CNS) manifestations. Both primary HSV infection and subsequent reactivation events can cause viral replication and spread within the brain, ultimately leading to pathologic inflammation and direct CNS damage. In addition to fulminant presentations of HSV encephalitis, subclinical HSV CNS infections have been implicated in neurodevelopmental, cognitive, and neurodegenerative impairment. To model the lifelong effects of subclinical HSV infection, we infected neonatal mice with low doses of HSV and studied lasting CNS impairment associated with infection. We found that low-dose HSV infection of neonatal mice resulted in persistent CNS infection and lasting behavioral and cognitive deficits. In an ex vivo model of infection, HSV infection of mouse embryonic hippocampal neurons led to intraneuronal accumulation of beta-amyloid, suggesting that HSV may contribute to cellular neurodegeneration pathways as well as behavioral pathology. Using mutant strains of HSV-1 and transgenic mice, we found that HSV-driven neurologic impairment is dependent on autophagy inhibition by the HSV infected cell protein (ICP)34.5 Beclin-1-binding domain (BBD) and exacerbated by expression of human apolipoprotein E e4 (ApoE4). Finally, we demonstrated how HSV viral genetics can contribute to adverse infection outcomes through an accidental discovery of a novel laboratory HSV-1 strain, strain R. Together, the data described in this thesis establishes a model for studying HSV-driven neuroimpairment, addresses a mechanism of viral damage following neonatal HSV infection, and explores both host and viral genetic factors that may confer increased susceptibility to HSV-induced neurodegeneration. Identifying the mechanisms of HSV-associated CNS damage, and the populations at highest risk for neurological morbidity, is essential for understanding the role viruses play in neurological diseases, such as Alzheimer’s Disease (AD). Through these studies, we hope to inform the development of novel treatments for HSV infection and AD and motivate continued research on the relationship between early-life viral exposures and neurodegeneration.
Recommended Citation
Dutton, Abigail Jeanne, "A Virus of the Mind: The Neurological Impact of Neonatal Herpes Simplex Virus Infection" (2025). Dartmouth College Ph.D Dissertations. 357.
https://digitalcommons.dartmouth.edu/dissertations/357
