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Title page for ETD etd-12042012-192214


Type of Document Dissertation
Author Doyle, Joshua David
Author's Email Address joshua.d.doyle@vanderbilt.edu
URN etd-12042012-192214
Title Reovirus Capsid Stability and Disease Pathogenesis
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
John Williams Committee Chair
Christopher AIken Committee Member
Earl Ruley Committee Member
Jennifer Pietenpol Committee Member
Terence Dermody Committee Member
Keywords
  • viral disassembly
  • myocarditis
  • transmission
  • cell entry
Date of Defense 2012-09-25
Availability unrestricted
Abstract
A common feature of nonenveloped virus replication is the requirement for structural capsid rearrangements to facilitate productive cell entry. Using mammalian orthoreovirus as a model, my work has focused on defining molecular features that determine the stability of viral outer-capsid structures and influence their interplay with host-cell mediators of infection. The initial event in reovirus disassembly is the proteolytic processing of outer-capsid protein σ3 by host endosomal cathepsin proteases. I identified a pair of residues in σ3 that act in opposition to control the rate of σ3 proteolysis, in turn influencing reovirus sensitivity to protease inhibitors. Moreover, I found that accelerated σ3 proteolysis correlates with diminished particle stability. Surprisingly, viruses with accelerated disassembly kinetics replicate more rapidly in the organs of infected mice, causing increased morbidity and mortality. Furthermore, reovirus variants with accelerated disassembly kinetics induce exaggerated myocarditis in infected animals, suggesting protease utilization may influence reovirus tissue tropism. Finally, I found that diminishing reovirus outer-capsid stability results in enhanced transmission between littermates. Together, this work furthers an understanding of the molecular mechanisms that determine reovirus protease sensitivity and establishes outer capsid stability as a determinant of nonenveloped virus pathogenesis and host-to-host spread.
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