Cargando…
A Molecular Determinant of West Nile Virus Secretion and Morphology as a Target for Viral Attenuation
West Nile virus (WNV), a member of the Flavivirus genus and currently one of the most common arboviruses worldwide, is associated with severe neurological disease in humans. Its high potential to reemerge and rapidly disseminate makes it a bona fide global public health problem. The surface membrane...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307099/ https://www.ncbi.nlm.nih.gov/pubmed/32269117 http://dx.doi.org/10.1128/JVI.00086-20 |
_version_ | 1783548763300691968 |
---|---|
author | Basset, Justine Burlaud-Gaillard, Julien Feher, Maxence Roingeard, Philippe Rey, Félix A. Pardigon, Nathalie |
author_facet | Basset, Justine Burlaud-Gaillard, Julien Feher, Maxence Roingeard, Philippe Rey, Félix A. Pardigon, Nathalie |
author_sort | Basset, Justine |
collection | PubMed |
description | West Nile virus (WNV), a member of the Flavivirus genus and currently one of the most common arboviruses worldwide, is associated with severe neurological disease in humans. Its high potential to reemerge and rapidly disseminate makes it a bona fide global public health problem. The surface membrane glycoprotein (M) has been associated with Flavivirus-induced pathogenesis. Here, we identified a key amino acid residue at position 36 of the M protein whose mutation impacts WNV secretion and promotes viral attenuation. We also identified a compensatory site at position M-43 whose mutation stabilizes M-36 substitution both in vitro and in vivo. Moreover, we found that introduction of the two mutations together confers a full attenuation phenotype and protection against wild-type WNV lethal challenge, eliciting potent neutralizing-antibody production in mice. Our study thus establishes the M protein as a new viral target for rational design of attenuated WNV strains. IMPORTANCE West Nile virus (WNV) is a worldwide (re)emerging mosquito-transmitted Flavivirus causing fatal neurological diseases in humans. However, no human vaccine has been yet approved. One of the most effective live-attenuated vaccines was empirically obtained by serial passaging of wild-type yellow fever Flavivirus. However, such an approach is not acceptable nowadays, and the development of a rationally designed vaccine is necessary. Generating molecular infectious clones and mutating specific residues known to be involved in Flavivirus virulence constitute a powerful tool to promote viral attenuation. WNV membrane glycoprotein is thought to carry such essential determinants. Here, we identified two residues of this protein whose substitutions are key to the full and stable attenuation of WNV in vivo, most likely through inhibition of secretion and possible alteration of morphology. Applied to other flaviviruses, this approach should help in designing new vaccines against these viruses, which are an increasing threat to global human health. |
format | Online Article Text |
id | pubmed-7307099 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-73070992020-07-10 A Molecular Determinant of West Nile Virus Secretion and Morphology as a Target for Viral Attenuation Basset, Justine Burlaud-Gaillard, Julien Feher, Maxence Roingeard, Philippe Rey, Félix A. Pardigon, Nathalie J Virol Virus-Cell Interactions West Nile virus (WNV), a member of the Flavivirus genus and currently one of the most common arboviruses worldwide, is associated with severe neurological disease in humans. Its high potential to reemerge and rapidly disseminate makes it a bona fide global public health problem. The surface membrane glycoprotein (M) has been associated with Flavivirus-induced pathogenesis. Here, we identified a key amino acid residue at position 36 of the M protein whose mutation impacts WNV secretion and promotes viral attenuation. We also identified a compensatory site at position M-43 whose mutation stabilizes M-36 substitution both in vitro and in vivo. Moreover, we found that introduction of the two mutations together confers a full attenuation phenotype and protection against wild-type WNV lethal challenge, eliciting potent neutralizing-antibody production in mice. Our study thus establishes the M protein as a new viral target for rational design of attenuated WNV strains. IMPORTANCE West Nile virus (WNV) is a worldwide (re)emerging mosquito-transmitted Flavivirus causing fatal neurological diseases in humans. However, no human vaccine has been yet approved. One of the most effective live-attenuated vaccines was empirically obtained by serial passaging of wild-type yellow fever Flavivirus. However, such an approach is not acceptable nowadays, and the development of a rationally designed vaccine is necessary. Generating molecular infectious clones and mutating specific residues known to be involved in Flavivirus virulence constitute a powerful tool to promote viral attenuation. WNV membrane glycoprotein is thought to carry such essential determinants. Here, we identified two residues of this protein whose substitutions are key to the full and stable attenuation of WNV in vivo, most likely through inhibition of secretion and possible alteration of morphology. Applied to other flaviviruses, this approach should help in designing new vaccines against these viruses, which are an increasing threat to global human health. American Society for Microbiology 2020-06-01 /pmc/articles/PMC7307099/ /pubmed/32269117 http://dx.doi.org/10.1128/JVI.00086-20 Text en Copyright © 2020 Basset et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Virus-Cell Interactions Basset, Justine Burlaud-Gaillard, Julien Feher, Maxence Roingeard, Philippe Rey, Félix A. Pardigon, Nathalie A Molecular Determinant of West Nile Virus Secretion and Morphology as a Target for Viral Attenuation |
title | A Molecular Determinant of West Nile Virus Secretion and Morphology as a Target for Viral Attenuation |
title_full | A Molecular Determinant of West Nile Virus Secretion and Morphology as a Target for Viral Attenuation |
title_fullStr | A Molecular Determinant of West Nile Virus Secretion and Morphology as a Target for Viral Attenuation |
title_full_unstemmed | A Molecular Determinant of West Nile Virus Secretion and Morphology as a Target for Viral Attenuation |
title_short | A Molecular Determinant of West Nile Virus Secretion and Morphology as a Target for Viral Attenuation |
title_sort | molecular determinant of west nile virus secretion and morphology as a target for viral attenuation |
topic | Virus-Cell Interactions |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307099/ https://www.ncbi.nlm.nih.gov/pubmed/32269117 http://dx.doi.org/10.1128/JVI.00086-20 |
work_keys_str_mv | AT bassetjustine amoleculardeterminantofwestnilevirussecretionandmorphologyasatargetforviralattenuation AT burlaudgaillardjulien amoleculardeterminantofwestnilevirussecretionandmorphologyasatargetforviralattenuation AT fehermaxence amoleculardeterminantofwestnilevirussecretionandmorphologyasatargetforviralattenuation AT roingeardphilippe amoleculardeterminantofwestnilevirussecretionandmorphologyasatargetforviralattenuation AT reyfelixa amoleculardeterminantofwestnilevirussecretionandmorphologyasatargetforviralattenuation AT pardigonnathalie amoleculardeterminantofwestnilevirussecretionandmorphologyasatargetforviralattenuation AT bassetjustine moleculardeterminantofwestnilevirussecretionandmorphologyasatargetforviralattenuation AT burlaudgaillardjulien moleculardeterminantofwestnilevirussecretionandmorphologyasatargetforviralattenuation AT fehermaxence moleculardeterminantofwestnilevirussecretionandmorphologyasatargetforviralattenuation AT roingeardphilippe moleculardeterminantofwestnilevirussecretionandmorphologyasatargetforviralattenuation AT reyfelixa moleculardeterminantofwestnilevirussecretionandmorphologyasatargetforviralattenuation AT pardigonnathalie moleculardeterminantofwestnilevirussecretionandmorphologyasatargetforviralattenuation |