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Title page for ETD etd-10202006-172315


Type of Document Dissertation
Author Hansberger, Mark William
Author's Email Address mark.hansberger@vanderbilt.edu
URN etd-10202006-172315
Title Viral and cellular determinants of reovirus-induced NF-kB activation and apoptosis
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Sebastian Joyce Committee Chair
Bruce Carter Committee Member
Christopher Aiken Committee Member
Dean W. Ballard Committee Member
Terence S. Dermody Committee Member
Keywords
  • myocarditis
  • apoptosis
  • NF-kB activation
  • reovirus
  • innate immunity
  • Apoptosis
  • Reoviruses
  • NF-kappa B (DNA-binding protein)
  • Virus diseases -- Pathogenesis
Date of Defense 2006-10-13
Availability unrestricted
Abstract
Mammalian reoviruses serve as important models for studies of viral replication and pathogenesis. These viruses have been isolated from many mammalian species, including humans, and cause disease primarily in the very young. Reoviruses induce apoptosis by engagement of cell-surface receptors, intracellular signal transduction, and activation of nuclear factor-kB (NF-kB). However, receptor binding alone is not sufficient to evoke these events. Internalization of reovirus by antibody-mediated uptake into Fc-receptor expressing cells indicates a critical function for the membrane penetration protein, mu1, in NF-kB activation and apoptosis. Reovirus activates NF-kB by stimulation of the multisubunit IkB kinase complex (IKK) resulting in phosphorylation and degradation of IkB alpha. Experiments using genetically deficient cell lines indicate a key role for the alpha and gamma IKK subunits in the mechanism used by reovirus to activate NF-kB. Mice lacking the NF-kB p50 subunit display diminished apoptosis in the brain following reovirus infection but enhanced apoptosis in the heart. IFN-alpha is upregulated following reovirus-induced NF-kB activation and protects cardiac myocytes against viral infection in cell culture and in vivo. Collectively, these findings identify both viral and cellular determinants of reovirus-induced apoptosis and define a novel mechanism employed by reovirus to cause disease in the infected host.
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