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A Single Amino Acid Substitution in Structural Protein VP2 Abrogates the Neurotropism of Enterovirus A-71 in Mice

Enterovirus 71 (EV-A71) causes hand, foot, and mouth disease (HFMD) in children and has been associated with neurological complications. With no specific treatment and a monovalent vaccine limited to the Chinese market, HFMD remains a serious public health concern and an economic burden to affected...

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Autores principales: Yeo, Huimin, Chong, Connie Wan Hui, Chen, Elijah Weihua, Lim, Ze Qin, Ng, Qing Yong, Yan, Benedict, Chu, Justin Jang Hann, Chow, Vincent T. K., Alonso, Sylvie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8969769/
https://www.ncbi.nlm.nih.gov/pubmed/35369482
http://dx.doi.org/10.3389/fmicb.2022.821976
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author Yeo, Huimin
Chong, Connie Wan Hui
Chen, Elijah Weihua
Lim, Ze Qin
Ng, Qing Yong
Yan, Benedict
Chu, Justin Jang Hann
Chow, Vincent T. K.
Alonso, Sylvie
author_facet Yeo, Huimin
Chong, Connie Wan Hui
Chen, Elijah Weihua
Lim, Ze Qin
Ng, Qing Yong
Yan, Benedict
Chu, Justin Jang Hann
Chow, Vincent T. K.
Alonso, Sylvie
author_sort Yeo, Huimin
collection PubMed
description Enterovirus 71 (EV-A71) causes hand, foot, and mouth disease (HFMD) in children and has been associated with neurological complications. With no specific treatment and a monovalent vaccine limited to the Chinese market, HFMD remains a serious public health concern and an economic burden to affected societies. The molecular mechanisms underpinning EV-A71 neurovirulence have yet to be fully elucidated. In this work, we provide experimental evidence that a single amino acid substitution (I to K) at position 149 in structural protein VP2 of a non-mouse-adapted EV-A71 strain completely and specifically abrogated its infectivity in murine motor neuron-like NSC-34 cells. We showed that VP2 I149K mutant was impaired in murine SCARB2-mediated entry step but retained the ability to attach at the cell surface. In vivo, VP2 I149K mutant was fully attenuated in a symptomatic mouse model of progressive limb paralysis. While viral titers in limb muscles were comparable to mice infected with parental wild-type strain, significantly lower viral titers were measured in the spinal cord and brain, with minimal tissue damage, therefore indicating that VP2 I149K mutant is specifically impaired in its ability to invade the central nervous system (CNS). This study highlights the key role of amino acid at position 149 in VP2 in EV-A71 neurovirulence, and lends further support that the EF loop of VP2 represents a potential therapeutic target.
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spelling pubmed-89697692022-04-01 A Single Amino Acid Substitution in Structural Protein VP2 Abrogates the Neurotropism of Enterovirus A-71 in Mice Yeo, Huimin Chong, Connie Wan Hui Chen, Elijah Weihua Lim, Ze Qin Ng, Qing Yong Yan, Benedict Chu, Justin Jang Hann Chow, Vincent T. K. Alonso, Sylvie Front Microbiol Microbiology Enterovirus 71 (EV-A71) causes hand, foot, and mouth disease (HFMD) in children and has been associated with neurological complications. With no specific treatment and a monovalent vaccine limited to the Chinese market, HFMD remains a serious public health concern and an economic burden to affected societies. The molecular mechanisms underpinning EV-A71 neurovirulence have yet to be fully elucidated. In this work, we provide experimental evidence that a single amino acid substitution (I to K) at position 149 in structural protein VP2 of a non-mouse-adapted EV-A71 strain completely and specifically abrogated its infectivity in murine motor neuron-like NSC-34 cells. We showed that VP2 I149K mutant was impaired in murine SCARB2-mediated entry step but retained the ability to attach at the cell surface. In vivo, VP2 I149K mutant was fully attenuated in a symptomatic mouse model of progressive limb paralysis. While viral titers in limb muscles were comparable to mice infected with parental wild-type strain, significantly lower viral titers were measured in the spinal cord and brain, with minimal tissue damage, therefore indicating that VP2 I149K mutant is specifically impaired in its ability to invade the central nervous system (CNS). This study highlights the key role of amino acid at position 149 in VP2 in EV-A71 neurovirulence, and lends further support that the EF loop of VP2 represents a potential therapeutic target. Frontiers Media S.A. 2022-03-17 /pmc/articles/PMC8969769/ /pubmed/35369482 http://dx.doi.org/10.3389/fmicb.2022.821976 Text en Copyright © 2022 Yeo, Chong, Chen, Lim, Ng, Yan, Chu, Chow and Alonso. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Yeo, Huimin
Chong, Connie Wan Hui
Chen, Elijah Weihua
Lim, Ze Qin
Ng, Qing Yong
Yan, Benedict
Chu, Justin Jang Hann
Chow, Vincent T. K.
Alonso, Sylvie
A Single Amino Acid Substitution in Structural Protein VP2 Abrogates the Neurotropism of Enterovirus A-71 in Mice
title A Single Amino Acid Substitution in Structural Protein VP2 Abrogates the Neurotropism of Enterovirus A-71 in Mice
title_full A Single Amino Acid Substitution in Structural Protein VP2 Abrogates the Neurotropism of Enterovirus A-71 in Mice
title_fullStr A Single Amino Acid Substitution in Structural Protein VP2 Abrogates the Neurotropism of Enterovirus A-71 in Mice
title_full_unstemmed A Single Amino Acid Substitution in Structural Protein VP2 Abrogates the Neurotropism of Enterovirus A-71 in Mice
title_short A Single Amino Acid Substitution in Structural Protein VP2 Abrogates the Neurotropism of Enterovirus A-71 in Mice
title_sort single amino acid substitution in structural protein vp2 abrogates the neurotropism of enterovirus a-71 in mice
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8969769/
https://www.ncbi.nlm.nih.gov/pubmed/35369482
http://dx.doi.org/10.3389/fmicb.2022.821976
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