Dissertation/Thesis Abstract

Mechanisms of Reovirus Serotype-Specific Type-1 Interferon Activation
by Stuart, Johnasha Donna, Ph.D., University of Arkansas for Medical Sciences, 2018, 199; 10813687
Abstract (Summary)

Mammalian orthoreoviruses (reoviruses) are nonenveloped viruses with segmented dsRNA genomes. Although infection with reovirus is largely asymptomatic in humans, recent evidence suggests that reovirus may contribute to loss of dietary immune tolerance, which can trigger celiac disease. Reovirus infection activates innate immune responses, such as type 1-interferons (IFNs). Although serotype 1 (T1) and serotype 3 (T3) reoviruses use similar mechanisms to enter host cells, the two serotypes differ in their capacity to induce IFNs. T3 reovirus elicit stronger IFN responses than T1 strains. We found that in SV-40 immortalized endothelial cells (SVECs), virion disassembly in endosomes is required for IFN activation. However, gene expression is not. Differences in IFN induction between T1 and T3 reoviruses correlates with the capacity to activate interferon regulatory factory 3 (IRF3) and NF-κB, two key transcription factors required for IFN production. Purified RNA from T1 and T3 reoviruses can activate IRF3, indicating that genomic RNA from both strains can trigger the IFN pathway. Our findings suggest that differences in IRF3 activation by T1 and T3 reoviruses in SVECs do not result from variability in RNA structure or disruption of IRF3 activation. Instead, differential delivery of genomic RNA into the cytosol by T1 and T3 leads to differences in innate immune activation. Reovirus serotypes also differentially activate cell death pathways. T3 induces significant apoptosis, whereas T1 kill cells through a non-apoptotic mechanism. Cell death gene array analysis revealed that T1 infection induced expression of genes involved in apoptosis, autophagy, and necrosis. Further, the T3 M2 gene encoding the membrane penetration protein ?1, influences pathogenesis of the T1 reovirus. The T3 M2 gene significantly increased replication, myocardial disease, and virulence by the T1 reovirus presumably due to increased apoptosis. These studies provide insights to further elucidate reovirus serotype-specific differences in IFN activation and cell death induction, and how both pathways interplay to cause reovirus-mediated pathogenesis.

Indexing (document details)
Advisor: Boehme, Karl W.
Commitee: Chambers, Timothy C., Forrest, James C., Liu, Jia, Xuming, Zhang
School: University of Arkansas for Medical Sciences
Department: Microbiology and Immunology
School Location: United States -- Arkansas
Source: DAI-B 79/10(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Microbiology, Virology, Immunology
Keywords: Double-stranded rna virus, Irf3, Recombinant virus, Reovirus, Type-1 interferon
Publication Number: 10813687
ISBN: 9780438037557
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