Publikationsdatenbank

Attenuation of Getah virus by a single amino acid substitution at residue 253 of the E2 protein that might be part of a new heparan sulfate binding site on alphaviruses (2022)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Wang, Ningning

Zhai, Xiaofeng

Li, Xiaoling

Wang, Yu

He, Wan-Ting

Jiang, Zhiwen

Veit, Michael (WE 5)

Su, Shuo

Quelle

Journal of virology : publ. by the American Society for Microbiology

Bandzählung: 96

Heftzählung: 6

Seiten: Artikel e01751-21

ISSN: 1098-5514

Sprache

Englisch

Verweise

URL (Volltext): https://journals.asm.org/doi/10.1128/jvi.01751-21

DOI: 10.1128/jvi.01751-21

Pubmed: 34986000

Kontakt

Institut für Virologie

Robert-von-Ostertag-Str. 7-13
14163 Berlin
+49 30 838 51833
virologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

The emergence of new epidemic variants of alphaviruses poses a public health risk. It is associated with adaptive mutations that often cause increased pathogenicity. Getah virus (GETV), a neglected and re-emerging mosquito-borne alphavirus, poses threat to many domestic animals and probably even humans. At present, the underlying mechanisms of GETV pathogenesis are not well defined. We identified a residue in the E2 glycoprotein that is critical for viral adsorption to cultured cells and pathogenesis in vivo. Viruses containing an arginine instead of a lysine at residue 253 displayed enhanced infectivity in mammalian cells and diminished virulence in a mouse model of GETV disease. Experiments in cell culture show that heparan sulfate (HS) is a new attachment factor for GETV, and the exchange Lys253Arg improves virus attachment by enhancing binding to HS. The mutation also results in more effective binding to glycosaminoglycan (GAG), linked to low virulence due to rapid virus clearance from the circulation. Localization of residue 253 in the three-dimensional structure of the spike revealed several other basic residues in E2 and E1 in close vicinity that might constitute an HS-binding site different from sites previously identified in other alphaviruses. Overall, our study reveals that HS acts as the attachment factor of GETV and provides convincing evidence for an HS-binding determinant at residue 253 in the E2 glycoprotein of GETV, which contributes to infectivity and virulence.