College of Science and Health Theses and Dissertations

Date of Award

Spring 6-13-2025

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Biological Science

First Advisor

Sarah Connolly, PhD

Second Advisor

Eiron Cudaback, PhD

Third Advisor

Joanna Brooke, PhD

Abstract

Herpes simplex virus type 1 (HSV-1) is a neurotropic virus that has been detected in brains affected by Alzheimer’s Disease (AD), the leading global cause of cognitive decline. In vitro and epidemiological studies support a role for HSV-1 in AD. The strongest genetic risk factor for late-onset AD is the E4 allele of APOE, which codes for apolipoprotein-E (ApoE), a protein that mediates brain cholesterol homeostasis. Previous work has suggested that ApoE can affect HSV-1 entry into cells; however, APOE has three alleles (E2, E3, and E4) and allelespecific effects of ApoE on HSV-1 entry remain undetermined. We hypothesized that ApoE-E4 enhances HSV-1 entry into cells by incorporating into virus particles and promoting host cell attachment via heparan sulfate. This hypothesis was tested using a virus-cell binding assay, a virus entry assay, and a virus incorporation assay. While an allele-specific effect of ApoE on HSV-1 entry into cells was unable to be fully elucidated, ApoE was not found to incorporate into HSV-1 particles produced by murine astrocytes, indicating that this model of ApoE-E4-enhanced HSV-1 entry was unlikely. Chronic neuroinflammation is a hallmark of AD, and HSV-1 infection induces robust immune signaling. Therefore, a second hypothesis was formulated that HSV-1 infection contributes to AD development by synergizing with APOE4 genotype to elicit elevated immune responses. To explore the impact of APOE genotype on the innate immune response to HSV-1, primary cultures of murine astrocytes humanized for APOE3 or APOE4 were exposed to virus, and cytokine expression was characterized by qRT-PCR. HSV-1 infection stimulated increased CCL-2, CXCL2, and IL-6 mRNA in APOE4 astrocytes compared to APOE3 astrocytes. This finding supports a model in which virus-induced innate immunity contributes to the elevated AD risk associated with HSV-1 infection and APOE4 genotype.

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