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Chikungunya virus binds sulfated glycosaminoglycans as attachment factors using specific residues in the E2 glycoprotein

McAllister, Nicole M (2021) Chikungunya virus binds sulfated glycosaminoglycans as attachment factors using specific residues in the E2 glycoprotein. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Chikungunya virus (CHIKV) is an arthritogenic alphavirus that causes a debilitating musculoskeletal disease. Currently, there are no vaccines or antiviral agents licensed to treat CHIKV disease. Studying the host requirements for CHIKV infection, such as cell attachment factors, may inform the development of therapeutics. Some CHIKV strains depend on cell-surface glycosaminoglycans (GAGs) for efficient infection. However, the specific types of GAGs and other glycans to which CHIKV binds is not fully understood. Using glycan microarray analyses with virus-like particles, we found that CHIKV preferentially binds GAGs relative to nine other glycan groups. Results indicate that sulfate groups on GAGs are essential for CHIKV binding, and CHIKV binds to GAGs as a function of chain length. We determined that strains representing all three CHIKV clades displayed dependence on GAGs for efficient cell-binding, which varied slightly by strain. Enzymatic cleavage of cell-surface GAGs and genetic alterations that diminish GAG expression result in diminished binding and infectivity. Additionally, alanine mutagenesis of the viral attachment protein, E2, enabled the identification of eight E2 residues required for GAG binding, three of which that are required for Mxra8 entry receptor binding. Future work will use these low GAG-binding mutant viruses to test the importance of GAG-binding in a mouse model of CHIKV infection. Collectively, these studies provide evidence for a critical function of GAGs in CHIKV infection, begin to define the GAG-binding region on the virus, and contribute new knowledge about the engagement of host cells by CHIKV.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
McAllister, Nicole Mnim85@pitt.edunim850000-0002-2453-3317
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorDermody, Terencetdermody@pitt.edu
Committee ChairLakdawala, Seemaseemal@pitt.edu
Committee MemberHartman, Amyhartman2@pitt.edu
Committee MemberGronenborn, Angelaamg100@pitt.edu
Committee MemberKlimstra, Williamklimstra@pitt.edu
Date: 10 May 2021
Date Type: Publication
Defense Date: 17 March 2021
Approval Date: 10 May 2021
Submission Date: 27 April 2021
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 182
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: virology, glycobiology, virus-host interactions
Date Deposited: 11 May 2021 03:14
Last Modified: 11 May 2021 03:14
URI: http://d-scholarship.pitt.edu/id/eprint/40828

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