First Advisor

Hawkinson, Ann C.

Document Type

Dissertation

Date Created

5-2020

Department

College of Natural and Health Sciences, Biological Sciences, Biological Sciences Student Work

Abstract

Flaviviruses (family Flaviviridae, genus Flavivirus) comprise a diverse group of globally-distributed viruses that may specifically infect vertebrates, invertebrates, or both. Of those that can replicate in both invertebrates (such as ticks and mosquitoes) as well as vertebrates (such as mammals), many represent important human pathogens. Examples of these include dengue virus (DENV), which may cause severe hemorrhagic fevers, West Nile virus (WNV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV), all of which may cause febrile illness with neurologic involvement, and yellow fever virus (YFV), which may induce hepatic dysfunction. Given that these viruses (among others) are carried and transmitted by ubiquitous insects whose range is increasingly expanding, hundreds of thousands of individuals worldwide are annually infected and succumb to either disease or death. Further, despite monumental strides in molecular research and medical practice over the preceding decades, vaccines are limited, and treatment for those infected relies exclusively on supportive care. While there are many obstacles to overcome in developing effective vaccines and antiviral therapeutics, one particular challenge during flaviviral infection lies in differentiating which aspects of the innate immune response lead to viral clearance or persistence and which may induce various immunopathologies. To glean further understanding in this respect, the research outlined in this dissertation utilizes two unique rodent models to investigate properties of viral replication and immune gene expression during the early stages of infection with a rodent-borne flavivirus (Modoc virus; MODV). By first examining these features in the deer mouse (Peromyscus maniculatus), which serves as the putative reservoir host of the virus in nature, it was discovered that viral RNA could be detected from all of the tissues and fluids examined throughout the experimental duration while infectious virus could be only be recovered from the kidneys, spleen, liver, and brain at later timepoints. Concomitant with this, the profile of select immune genes (IFN-γ, TNFα, IL-6, IL-10, and TGFβ) were shown to be differentially expressed in the brain as compared to all other tissues. Likewise, expression profiles significantly differed at a collection timepoint midway through the experiment (day 6) compared to the first (day 1) and last (day 10) timepoint of collection, suggesting that deer mice respond to MODV infection through a tightly-regulated expression of innate immune genes that is both tissue- and time-dependent. These features were then compared to those observed in Syrian golden hamsters (Mesocricetus auratus), which, unlike the deer mice, develop illness with neurologic involvement reminiscent of some flaviviral infections in humans. In hamsters, the patterns of viral replication different from deer mice in that the levels of MODV RNA were lower in all tissues at the first collection timepoint but then surpassed the levels observed in deer mice by day 4 and generally remained elevated throughout the remainder of the experiment. Although infectious virus could only be recovered from the kidneys and spleens of infected hamsters, successful isolation was evident at all sampling timepoints suggesting that hamsters are less able to control the production of viral progeny in these tissues. In regard to gene expression, multivariate analysis depicts a differential expression of the important antiviral cytokine IFN-γ between deer mice and hamsters, a response which is especially evident in the brain tissue beginning at day 6 post-infection. This finding may represent a potential mechanism for immunopathology, which allows for increased viral dissemination into the CNS following the breakdown of vascular integrity after elevated proinflammatory signaling. All in all, there is hope that this research may contribute to the greater scientific community’s collective understanding of flaviviral pathology and provide a novel avenue to pursue in the development of antiviral therapeutics.

Extent

192 pages

Local Identifiers

Sherman_unco_0161D_10848.pdf

Comments

Spring 2020 Graduate Dean's Citation for Outstanding Thesis, Dissertation, and Scholarly Project

Rights Statement

Copyright is held by the author.

Download

Share

COinS