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A Single Amino Acid Substitution in the Core Protein of West Nile Virus Increases Resistance to Acidotropic Compounds

West Nile virus (WNV) is a worldwide distributed mosquito-borne flavivirus that naturally cycles between birds and mosquitoes, although it can infect multiple vertebrate hosts including horses and humans. This virus is responsible for recurrent epidemics of febrile illness and encephalitis, and has...

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Autores principales: Martín-Acebes, Miguel A., Blázquez, Ana-Belén, de Oya, Nereida Jiménez, Escribano-Romero, Estela, Shi, Pei-Yong, Saiz, Juan-Carlos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715472/
https://www.ncbi.nlm.nih.gov/pubmed/23874963
http://dx.doi.org/10.1371/journal.pone.0069479
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author Martín-Acebes, Miguel A.
Blázquez, Ana-Belén
de Oya, Nereida Jiménez
Escribano-Romero, Estela
Shi, Pei-Yong
Saiz, Juan-Carlos
author_facet Martín-Acebes, Miguel A.
Blázquez, Ana-Belén
de Oya, Nereida Jiménez
Escribano-Romero, Estela
Shi, Pei-Yong
Saiz, Juan-Carlos
author_sort Martín-Acebes, Miguel A.
collection PubMed
description West Nile virus (WNV) is a worldwide distributed mosquito-borne flavivirus that naturally cycles between birds and mosquitoes, although it can infect multiple vertebrate hosts including horses and humans. This virus is responsible for recurrent epidemics of febrile illness and encephalitis, and has recently become a global concern. WNV requires to transit through intracellular acidic compartments at two different steps to complete its infectious cycle. These include fusion between the viral envelope and the membrane of endosomes during viral entry, and virus maturation in the trans-Golgi network. In this study, we followed a genetic approach to study the connections between viral components and acidic pH. A WNV mutant with increased resistance to the acidotropic compound NH(4)Cl, which blocks organelle acidification and inhibits WNV infection, was selected. Nucleotide sequencing revealed that this mutant displayed a single amino acid substitution (Lys 3 to Glu) on the highly basic internal capsid or core (C) protein. The functional role of this replacement was confirmed by its introduction into a WNV infectious clone. This single amino acid substitution also increased resistance to other acidification inhibitor (concanamycin A) and induced a reduction of the neurovirulence in mice. Interestingly, a naturally occurring accompanying mutation found on prM protein abolished the resistant phenotype, supporting the idea of a genetic crosstalk between the internal C protein and the external glycoproteins of the virion. The findings here reported unveil a non-previously assessed connection between the C viral protein and the acidic pH necessary for entry and proper exit of flaviviruses.
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spelling pubmed-37154722013-07-19 A Single Amino Acid Substitution in the Core Protein of West Nile Virus Increases Resistance to Acidotropic Compounds Martín-Acebes, Miguel A. Blázquez, Ana-Belén de Oya, Nereida Jiménez Escribano-Romero, Estela Shi, Pei-Yong Saiz, Juan-Carlos PLoS One Research Article West Nile virus (WNV) is a worldwide distributed mosquito-borne flavivirus that naturally cycles between birds and mosquitoes, although it can infect multiple vertebrate hosts including horses and humans. This virus is responsible for recurrent epidemics of febrile illness and encephalitis, and has recently become a global concern. WNV requires to transit through intracellular acidic compartments at two different steps to complete its infectious cycle. These include fusion between the viral envelope and the membrane of endosomes during viral entry, and virus maturation in the trans-Golgi network. In this study, we followed a genetic approach to study the connections between viral components and acidic pH. A WNV mutant with increased resistance to the acidotropic compound NH(4)Cl, which blocks organelle acidification and inhibits WNV infection, was selected. Nucleotide sequencing revealed that this mutant displayed a single amino acid substitution (Lys 3 to Glu) on the highly basic internal capsid or core (C) protein. The functional role of this replacement was confirmed by its introduction into a WNV infectious clone. This single amino acid substitution also increased resistance to other acidification inhibitor (concanamycin A) and induced a reduction of the neurovirulence in mice. Interestingly, a naturally occurring accompanying mutation found on prM protein abolished the resistant phenotype, supporting the idea of a genetic crosstalk between the internal C protein and the external glycoproteins of the virion. The findings here reported unveil a non-previously assessed connection between the C viral protein and the acidic pH necessary for entry and proper exit of flaviviruses. Public Library of Science 2013-07-18 /pmc/articles/PMC3715472/ /pubmed/23874963 http://dx.doi.org/10.1371/journal.pone.0069479 Text en © 2013 Martín-Acebes et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Martín-Acebes, Miguel A.
Blázquez, Ana-Belén
de Oya, Nereida Jiménez
Escribano-Romero, Estela
Shi, Pei-Yong
Saiz, Juan-Carlos
A Single Amino Acid Substitution in the Core Protein of West Nile Virus Increases Resistance to Acidotropic Compounds
title A Single Amino Acid Substitution in the Core Protein of West Nile Virus Increases Resistance to Acidotropic Compounds
title_full A Single Amino Acid Substitution in the Core Protein of West Nile Virus Increases Resistance to Acidotropic Compounds
title_fullStr A Single Amino Acid Substitution in the Core Protein of West Nile Virus Increases Resistance to Acidotropic Compounds
title_full_unstemmed A Single Amino Acid Substitution in the Core Protein of West Nile Virus Increases Resistance to Acidotropic Compounds
title_short A Single Amino Acid Substitution in the Core Protein of West Nile Virus Increases Resistance to Acidotropic Compounds
title_sort single amino acid substitution in the core protein of west nile virus increases resistance to acidotropic compounds
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3715472/
https://www.ncbi.nlm.nih.gov/pubmed/23874963
http://dx.doi.org/10.1371/journal.pone.0069479
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