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Title page for ETD etd-07162015-174823


Type of Document Dissertation
Author Ashbrook, Alison Whitney
Author's Email Address alison.w.ashbrook@vanderbilt.edu
URN etd-07162015-174823
Title Unveiling Strategies for Chikungunya Virus Attenuation and Antiviral Therapy
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
John V. Williams Committee Chair
Christopher R. Aiken Committee Member
D. Borden Lacy Committee Member
James W. Thomas Committee Member
Sandra S. Zinkel Committee Member
Terence S. Dermody Committee Member
Keywords
  • sodium-potassium ATPase
  • digoxin
  • attachment
  • glycosaminoglycan
  • high-throughput screen
  • immunoproteasome
  • PSME2
  • arthritis
  • alphavirus
  • chikungunya virus
Date of Defense 2015-06-12
Availability unrestricted
Abstract
Chikungunya virus (CHIKV) is a mosquito-borne cause of epidemics of debilitating arthritis worldwide. Currently, there are no licensed vaccines or antiviral therapies available for the prevention or treatment of CHIKV disease. Furthermore, the viral and host determinants required for CHIKV replication and pathogenesis are not understood. Using chimeric viruses generated from virulent and attenuated CHIKV strains, I identified a single residue in the E2 viral attachment protein that serves as a critical determinant of CHIKV replication in cultured cells and pathogenesis in mice. I demonstrate that E2 residue 82 differentially influences infectivity in mammalian and mosquito cells and contributes to interactions with glycosaminoglycans (GAGs). Moreover, mice inoculated with GAG-dependent viruses displayed reduced inflammation in the joint and dissemination to sites of secondary replication. These findings indicate that E2 residue 82 modulates CHIKV dissemination and arthritis and suggest a function for GAG utilization in CHIKV attenuation. Using chemical compound and RNA interference screening approaches, I identified digoxin, an inhibitor of the sodium-potassium ATPase, and PSME2, a regulator of the immunoproteasome, as antagonists of CHIKV infection. Digoxin inhibited CHIKV at both entry and post-entry steps in the replication cycle and was effective against other alphaviruses. Knockdown of PSME2 or blockade of proteasome activity enhanced CHIKV infection. These data suggest roles for the sodium-potassium ATPase and immunoproteasome in CHIKV replication. Collectively, this work reveals mechanisms of CHIKV virulence and provides new targets for the development of CHIKV-specific and broad-spectrum antivirals.
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