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Identification of Cellular Factors Involved in Entry Medicated by the Ebolavirus Glycoprotein

Schornberg, Kathryn Lynn
Thesis/Dissertation; Online
Schornberg, Kathryn Lynn
Bouton, Amy
Casanova, Jim
Engel, Dan
Brown, Jay
Taylor, Ron
White, Judith
Ebolavirus causes a severe hemorrhagic fever disease in humans and nonhuman primates with mortalities of up to 90%. There are currently no approved vaccines or antivirals for the treatment of ebolavirus infections. Viruses are by nature obligatory intracellular parasites, therefore viral entry into a host cell is a critical stage in the life cycle of a virus and an attractive target for the design of antiviral treatments. Gaining insight into the mechanism and cellular factors involved in ebolavirus entry will help facilitate the design of these types of treatments. Studies on ebolavirus have been severely limited by the high biosafety level of containment needed to work with this virus. The development of pseudovirions that express the ebolavirus glycoprotein (GP) on the surface of an innocuous virus has helped to overcome this obstacle. Using this system, we have found that ebolavirus employs an apparently novel fusion mechanism in which the endosomal cysteine proteases cathepsin B and cathepsin L prime GP to a highly active intermediate. A second step, which may also be regulated by cathepsin L, is then required for fusion triggering. We have also found that cell adhesion molecules play an important role in ebolavirus entry. The susceptibility to infection with GP pseudotyped viruses and to binding by a soluble receptor binding region of GP is acquired with cell adhesion and spreading. This indicates that the receptor for ebolavirus is regulated by cell adhesion. In addition, we found that expression of α5β1 integrin is required for ebolavirus infection. However, it does not appear to be required for virus binding or internalization. Instead α5β1 integrin modulates the expression of endosomal cathepsins, and therefore ebolavirus fusion. This represents a novel role for integrins in virus entry that will likely apply to other viruses as well. Note: Abstract extracted from PDF text
University of Virginia, Department of Microbiology, PHD (Doctor of Philosophy), 2008
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PHD (Doctor of Philosophy)
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