A VP1 mutation acquired during an enterovirus 71 disseminated infection confers heparan sulfate binding ability and modulates ex vivo tropism

Tseligka, Eirini D. (Department of Microbiology and Molecular Medicine, University of Geneva Medical School, Geneva, Switzerland) ; Sobo, Komla (Department of Microbiology and Molecular Medicine, University of Geneva Medical School, Geneva, Switzerland) ; Stoppini, Luc (School of Engineering, Architecture and Landscape (hepia), HES-SO // University of Applied Sciences Western Switzerland) ; Cagno, Valeria (Department of Microbiology and Molecular Medicine, University of Geneva Medical School, Geneva, Switzerland) ; Abdul, Fabien (Department of Microbiology and Molecular Medicine, University of Geneva Medical School, Geneva, Switzerland) ; Piuz, Isabelle (Department of Microbiology and Molecular Medicine, University of Geneva Medical School, Geneva, Switzerland) ; Meylan, Pascal (Institute of Microbiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland) ; Huang, Song (Epithelix Sàrl, Geneva, Switzerland) ; Constant, Samuel (Epithelix Sàrl, Geneva, Switzerland) ; Tapparel, Caroline (Department of Microbiology and Molecular Medicine, University of Geneva Medical School, Geneva, Switzerland)

Article Authors Metrics Comments Media Coverage Abstract Author summary Introduction Results Discussion Materials and methods Supporting information Acknowledgments References Reader Comments (0) Media Coverage (0) Figures Abstract Enterovirus 71 (EV71) causes hand, foot and mouth disease, a mild and self-limited illness that is sometimes associated with severe neurological complications. EV71 neurotropic determinants remain ill-defined to date. We previously identified a mutation in the VP1 capsid protein (L97R) that was acquired over the course of a disseminated infection in an immunocompromised host. The mutation was absent in the respiratory tract but was present in the gut (as a mixed population) and in blood and cerebrospinal fluid (as a dominant species). In this study, we demonstrated that this mutation does not alter the dependence of EV71 on the human scavenger receptor class B2 (SCARB2), while it enables the virus to bind to the heparan sulfate (HS) attachment receptor and modifies viral tropism in cell lines and in respiratory, intestinal and neural tissues. Variants with VP197L or VP197R were able to replicate to high levels in intestinal and neural tissues and, to a lesser extent, in respiratory tissues, but their preferred entry site (from the luminal or basal tissue side) differed in respiratory and intestinal tissues and correlated with HS expression levels. These data account for the viral populations sequenced from the patient’s respiratory and intestinal samples and suggest that improved dissemination, resulting from an acquired ability to bind HS, rather than specific neurotropism determinants, enabled the virus to reach and infect the central nervous system. Finally, we showed that iota-carrageenan, a highly sulfated polysaccharide, efficiently blocks the replication of HS-dependent variants in cells and 2D neural cultures. Overall, the results of this study emphasize the importance of HS binding in EV71 pathogenesis and open new avenues for the development of antiviral molecules that may prevent this virus’s dissemination.


Keywords:
Article Type:
scientifique
Faculty:
Ingénierie et Architecture
School:
HEPIA - Genève
Institute:
inSTI - Institut des Sciences et Technologies industrielles
Date:
2018-08
Pagination:
25 p.
Published in:
PLOS Pathogens
Numeration (vol. no.):
2018, vol. 14, no. 8, article no. e1007190
DOI:
ISSN:
1553-7374
Appears in Collection:



 Record created 2020-08-25, last modified 2020-10-27

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