Journal Article

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

Constant, Samuel, Sobo, Komla, Huang, Song, Tapparel, Caroline, Stoppini, Luc, Cagno, Valeria, Abdul, Fabien, Meylan, Pascal, Piuz, Isabelle, Tseligka, Eirini D.

2018

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Binding / Biology and Life Sciences / Capsid protein / Capsid Proteins - genetics / Carrageenan / Cell lines / Central nervous system / Cerebrospinal fluid / Complications / Dependence / Disease control / Disseminated infection / Dominant species / Enterovirus A, Human - pathogenicity / Enterovirus A, Human - physiology / Enteroviruses / Gene mutation / Gene mutations / Genetic aspects / Glycoproteins / Hand, Foot and Mouth Disease - genetics / Hand, Foot and Mouth Disease - metabolism / Hand, Foot and Mouth Disease - virology / Hand-foot-and-mouth disease / Heparan sulfate / Heparitin Sulfate - metabolism / Humans / Infections / Intestine / Lysosomal Membrane Proteins - metabolism / Medical schools / Medicine / Medicine and Health Sciences / Mice / Mutation / Nervous system / Neurological complications / Neurotropism / Pathogenesis / Physiological aspects / Polysaccharides / Receptors, Scavenger - metabolism / Research and Analysis Methods / Respiratory tract / Scavenger receptors / Stem cells / Sulfates / Tissues / Tropism / Viral Tropism - genetics / Virology / Virus Replication - genetics / Viruses / VP1 protein