A Study of the Ebola Virus Glycoprotein: Disruption of Host Surface Protein Function and Evasion of Immune Responses

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Doctor of Philosophy (PhD)
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Cell & Molecular Biology
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Ebola virus
glycan shield
MHC I
mucin
adhesion
viral glycoprotein
Virology
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Francica, Joseph R
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Abstract

The Ebola virus (EBOV) is a member of the family, Filoviridae, and is the etiological agent of Ebola hemorrhagic fever (EHF). This disease causes significant morbidity and mortality in humans and non-human primates, with human fatality rates reaching 90% during outbreaks of the Zaire subtype. Currently, there are no licensed vaccines or antivirals for EBOV and our understanding of viral pathogenesis is limited. Therefore, further studies examining the pathogenic mechanisms of EBOV are necessary to fully understand and effectively treat EHF. The main Ebola virus glycoprotein (GP) is the only viral protein found on the surface of the Ebola virion and is therefore responsible for mediating attachment and entry of the virus into host cells. However, expression of GP independently of other viral proteins induces dramatic morphological changes including cell rounding and detachment in those cells expressing GP. This phenomenon is referred to as GP-mediated cytopathology and is the focus of the work described herein. We have undertaken studies to identify the mucin domain, a highly glycosylated domain within GP, as sufficient to cause this cytopathology. We then have used a cell-biological approach to elucidate the mechanism by which this cytopathology occurs. The mucin domain forms a glycan shield at the plasma membrane, disrupting the function of host proteins in the vicinity of GP. We then show that GP-mediated shielding of major histocompatibility complex class I at the cell surface prevents the activation of CD 8+ T cells. Additionally, GP can sterically shield its own epitopes at the cell surface. This model of steric hindrance was also found to apply to the surface of pseudoviral particles, where access to a neutralizing epitope on GP is affected. Our data indicate that the EBOV GP forms a glycan shield with the ability to block antibody binding and disrupt protein function at the cell and virion surface. This study describes a novel viral mechanism for the disruption of surface protein function and suggests a possible mechanism for the evasion of host humoral and cellular immune responses.

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Paul Bates, Ph.D.
Date of degree
2010-08-13
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