Date of Award

2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Microbiology, Immunology, and Biochemistry

Research Advisor

Stacey Schultz-Cherry, PhD

Committee

Diego Hijano, MD, Msc; Elaine Tuomanen, MD; Jason Rosch, PhD; Michael Whitt, PhD

Keywords

Astrovirus, CNS Disease, Neurovirology

Abstract

Central nervous system (CNS) diseases caused by infectious agents pose significant health challenges, often leading to severe neurological dysfunction with high morbidity and mortality rates. Astroviruses (AstVs), traditionally known for causing gastroenteritis, have recently been identified as neuroinvasive pathogens capable of inducing neurological diseases. This study explores the cellular and molecular mechanisms by which AstV, specifically non-classical VA1 and classical HAstV1 genotypes, induce CNS pathology in human neurons and astrocytes. Utilizing primary human neurons and astrocytes from various brain regions, this research investigates the cytotoxic effects, apoptotic pathways, and inflammatory responses triggered by these viruses. This study reveals that VA1 exposure leads to significant cytotoxicity in neurons, marked by increased dead-cell protease activity and a substantial rise in caspase-3/7 activity, indicating apoptosis. Additionally, VA1 infection alters gene expression related to neurotoxicity and cell death, promoting apoptotic pathways and inflammatory responses, as evidenced by the up-regulation of cytokines such as IL-6, IL-8, and IFN-λ1. In astrocytes, VA1 infection results in region-specific morphological changes and cytotoxicity without significant caspase-3/7 activation, suggesting non-apoptotic cell death pathways. Contrarily, HAstV1 exposure in neurons does not induce notable apoptosis but leads to heightened cytotoxicity, implying a different mechanism of cell death. HAstV1 infection in astrocytes, however, increases caspase-3/7 activity, pointing towards apoptosis as a primary mode of cell death. The studies in this dissertation underscore the distinct cellular responses elicited by different AstV genotypes, highlighting the complexities of their interaction with CNS cells. The findings here provide foundational insights into the mechanisms of AstV-induced neurovirulence, essential for developing therapeutic strategies to manage AstV-associated CNS diseases.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

0000-0002-5519-6333

DOI

10.21007/etd.cghs.2024.0674

Additional Files
2024-017-Davis-DOA.pdf (168 kB)
Declaration of Authorship
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