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Chikungunya virus strains from each genetic clade bind sulfated glycosaminoglycans as attachment factors

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Title: Chikungunya virus strains from each genetic clade bind sulfated glycosaminoglycans as attachment factors
Authors: McAllister, N
Liu, Y
Silva, LM
Lentscher, AJ
Chai, W
Wu, N
Griswold, KA
Raghunathan, K
Vang, L
Alexander, J
Warfield, KL
Diamond, MS
Feizi, T
Silva, LA
Dermody, TS
Item Type: Journal Article
Abstract: Chikungunya virus (CHIKV) is an arthritogenic alphavirus that causes debilitating musculoskeletal disease. CHIKV displays broad cell, tissue, and species tropism, which may correlate with the attachment factors and entry receptors used by the virus. Cell-surface glycosaminoglycans (GAGs) have been identified as CHIKV attachment factors. However, the specific types of GAGs and potentially other glycans to which CHIKV binds and whether there are strain-specific differences in GAG binding is not fully understood. To identify the types of glycans bound by CHIKV, we conducted glycan microarray analyses and discovered that CHIKV preferentially binds GAGs. Microarray results also indicate that sulfate groups on GAGs are essential for CHIKV binding and that CHIKV binds most strongly to longer GAG chains of heparin and heparan sulfate. To determine whether GAG-binding capacity varies among CHIKV strains, a representative strain from each genetic clade was tested. While all strains directly bound to heparin and chondroitin sulfate in ELISAs and depended on heparan sulfate for efficient cell-binding and infection, we observed some variation by strain. Enzymatic removal of cell-surface GAGs and genetic ablation that diminishes GAG expression reduced CHIKV binding and infectivity of all strains. Collectively, these data demonstrate that GAGs are the preferred glycan bound by CHIKV, enhance our understanding of the specific GAG moieties required for CHIKV binding, define strain differences in GAG engagement, and provide further evidence for a critical function of GAGs in CHIKV cell attachment and infection.IMPORTANCE Alphavirus infections are a global health threat, contributing to outbreaks of disease in many parts of the world. Recent epidemics caused by CHIKV, an arthritogenic alphavirus, resulted in more than 8.5 million cases as the virus has spread into new geographic regions, including the Western Hemisphere. CHIKV causes disease in the majority of people infected, leading to severe and debilitating arthritis. Despite the severity of CHIKV disease, there are no licensed therapeutics. Since attachment factors and receptors are determinants of viral tropism and pathogenesis, understanding these virus-host interactions can enhance our knowledge of CHIKV infection. We analyzed over 670 glycans and identified GAGs as the main glycan bound by CHIKV. We defined specific GAG components required for CHIKV binding and assessed strain-specific differences in GAG-binding capacity. These studies provide insight about cell-surface molecules that CHIKV binds, which could facilitate the development of antiviral therapeutics targeting the CHIKV attachment step.
Issue Date: 1-Dec-2020
Date of Acceptance: 28-Sep-2020
URI: http://hdl.handle.net/10044/1/84261
DOI: 10.1128/JVI.01500-20
ISSN: 0022-538X
Publisher: American Society for Microbiology
Journal / Book Title: Journal of Virology
Volume: 94
Issue: 24
Copyright Statement: © 2020 McAllister et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: Wellcome Trust
Wellcome Trust
Funder's Grant Number: 108430/Z/15/Z
218304/Z/19/Z
Keywords: 06 Biological Sciences
07 Agricultural and Veterinary Sciences
11 Medical and Health Sciences
Virology
Publication Status: Published
Conference Place: United States
Article Number: ARTN 01500
Online Publication Date: 2020-11-23
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Faculty of Medicine



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