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Title page for ETD etd-09252012-170243


Type of Document Dissertation
Author Frierson, Johnna McKeeta
URN etd-09252012-170243
Title The Role of Sialic Acid Binding in Reovirus Neuropathogenesis
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Eric Skaar Committee Chair
Bruce Carter Committee Member
John Williams Committee Member
Terence S. Dermody Committee Member
Wonder Drake Committee Member
Keywords
  • neuropathogenesis
  • reovirus
  • dissemination
  • sialic acid
  • receptors
  • glycans
  • carbohydrates
Date of Defense 2012-09-13
Availability unrestricted
Abstract
The process by which viruses cause disease consists of a complex series of steps involving many host and viral factors. The first step in the viral replication cycle, attachment of the virus to cell-surface receptors, is important for establishing infection and serves a critical function in viral pathogenesis. Mammalian reoviruses, a highly tractable experimental model for the study of viral pathogenesis, display serotype-specific patterns of tropism and disease within the murine central nervous system (CNS) attributable to the viral attachment protein, σ1. While all reovirus serotypes engage the proteinaceous receptor junction adhesion molecule-A, these strains differ in carbohydrate coreceptor utilization, suggesting that carbohydrate binding by σ1 influences reovirus pathology in the CNS. However, mechanisms underlying reovirus spread to and within the CNS are not well understood. The goals of my research were to elucidate the molecular basis of sialic acid (SA) binding by T3 reovirus and define the contribution of SA engagement in reovirus target-cell selection and neuropathogenesis. First, I report the crystal structure of T3 σ1 in complex with sialylated oligosaccharides. Using structural information and mutagenesis studies, I defined a discrete network of residues in T3 σ1, centered on Arg202, that are required for SA binding. Furthermore, data gathered from in vivo experiments comparing strains that differ in the capacity to bind SA suggest that SA-binding enhances reovirus neurovirulence by allowing more efficient infection of CNS tissues. These findings reveal the structural and molecular basis of T3 σ1-SA interactions and suggest that SA-binding enhances reovirus infection of the murine CNS. Results from this research have enhanced an understanding of mechanisms of reovirus attachment to neuronal cells and the molecular interactions and structural features that mediate receptor engagement by viral attachment proteins. Knowledge of pathologic mechanisms gained from this research may establish general principles of viral neuropathogenesis, thereby improving our ability to develop antiviral therapeutics. Moreover, an enhanced understanding of the molecular interactions that occur between σ1 and its cellular receptors will aid in the continued development of reovirus as an oncolytic agent and vaccine vector.
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