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A natural polymorphism in Zika virus NS2A protein responsible of virulence in mice
Zika virus (ZIKV) infection is currently one of the major concerns in human public health due to its association with neurological disorders. Intensive effort has been implemented for the treatment of ZIKV, however there are not currently approved vaccines or antivirals available to combat ZIKV infe...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934710/ https://www.ncbi.nlm.nih.gov/pubmed/31882898 http://dx.doi.org/10.1038/s41598-019-56291-4 |
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author | Ávila-Pérez, Gines Nogales, Aitor Park, Jun-Gyu Márquez-Jurado, Silvia Iborra, Francisco J. Almazan, Fernando Martínez-Sobrido, Luis |
author_facet | Ávila-Pérez, Gines Nogales, Aitor Park, Jun-Gyu Márquez-Jurado, Silvia Iborra, Francisco J. Almazan, Fernando Martínez-Sobrido, Luis |
author_sort | Ávila-Pérez, Gines |
collection | PubMed |
description | Zika virus (ZIKV) infection is currently one of the major concerns in human public health due to its association with neurological disorders. Intensive effort has been implemented for the treatment of ZIKV, however there are not currently approved vaccines or antivirals available to combat ZIKV infection. In this sense, the identification of virulence factors associated with changes in ZIKV virulence could help to develop safe and effective countermeasures to treat ZIKV or to prevent future outbreaks. Here, we have compared the virulence of two related ZIKV strains from the recent outbreak in Brazil (2015), Rio Grande do Norte Natal (RGN) and Paraiba. In spite of both viruses being identified in the same period of time and region, significant differences in virulence and replication were observed using a validated mouse model of ZIKV infection. While ZIKV-RGN has a 50% mouse lethal dose (MLD(50)) of ~10(5) focus forming units (FFUs), ZIKV-Paraiba infection resulted in 100% of lethality with less than 10 FFUs. Combining deep-sequencing analysis and our previously described infectious ZIKV-RGN cDNA clone, we identified a natural polymorphism in the non-structural protein 2 A (NS2A) that increase the virulence of ZIKV. Moreover, results demonstrate that the single amino acid alanine to valine substitution at position 117 (A117V) in the NS2A was sufficient to convert the attenuated rZIKV-RGN in a virulent Paraiba-like virus (MLD(50) < 10 FFU). The mechanism of action was also evaluated and data indicate that substitution A117V in ZIKV NS2A protein reduces host innate immune responses and viral-induced apoptosis in vitro. Therefore, amino acid substitution A117V in ZIKV NS2A could be used as a genetic risk-assessment marker for future ZIKV outbreaks. |
format | Online Article Text |
id | pubmed-6934710 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-69347102019-12-30 A natural polymorphism in Zika virus NS2A protein responsible of virulence in mice Ávila-Pérez, Gines Nogales, Aitor Park, Jun-Gyu Márquez-Jurado, Silvia Iborra, Francisco J. Almazan, Fernando Martínez-Sobrido, Luis Sci Rep Article Zika virus (ZIKV) infection is currently one of the major concerns in human public health due to its association with neurological disorders. Intensive effort has been implemented for the treatment of ZIKV, however there are not currently approved vaccines or antivirals available to combat ZIKV infection. In this sense, the identification of virulence factors associated with changes in ZIKV virulence could help to develop safe and effective countermeasures to treat ZIKV or to prevent future outbreaks. Here, we have compared the virulence of two related ZIKV strains from the recent outbreak in Brazil (2015), Rio Grande do Norte Natal (RGN) and Paraiba. In spite of both viruses being identified in the same period of time and region, significant differences in virulence and replication were observed using a validated mouse model of ZIKV infection. While ZIKV-RGN has a 50% mouse lethal dose (MLD(50)) of ~10(5) focus forming units (FFUs), ZIKV-Paraiba infection resulted in 100% of lethality with less than 10 FFUs. Combining deep-sequencing analysis and our previously described infectious ZIKV-RGN cDNA clone, we identified a natural polymorphism in the non-structural protein 2 A (NS2A) that increase the virulence of ZIKV. Moreover, results demonstrate that the single amino acid alanine to valine substitution at position 117 (A117V) in the NS2A was sufficient to convert the attenuated rZIKV-RGN in a virulent Paraiba-like virus (MLD(50) < 10 FFU). The mechanism of action was also evaluated and data indicate that substitution A117V in ZIKV NS2A protein reduces host innate immune responses and viral-induced apoptosis in vitro. Therefore, amino acid substitution A117V in ZIKV NS2A could be used as a genetic risk-assessment marker for future ZIKV outbreaks. Nature Publishing Group UK 2019-12-27 /pmc/articles/PMC6934710/ /pubmed/31882898 http://dx.doi.org/10.1038/s41598-019-56291-4 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Ávila-Pérez, Gines Nogales, Aitor Park, Jun-Gyu Márquez-Jurado, Silvia Iborra, Francisco J. Almazan, Fernando Martínez-Sobrido, Luis A natural polymorphism in Zika virus NS2A protein responsible of virulence in mice |
title | A natural polymorphism in Zika virus NS2A protein responsible of virulence in mice |
title_full | A natural polymorphism in Zika virus NS2A protein responsible of virulence in mice |
title_fullStr | A natural polymorphism in Zika virus NS2A protein responsible of virulence in mice |
title_full_unstemmed | A natural polymorphism in Zika virus NS2A protein responsible of virulence in mice |
title_short | A natural polymorphism in Zika virus NS2A protein responsible of virulence in mice |
title_sort | natural polymorphism in zika virus ns2a protein responsible of virulence in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934710/ https://www.ncbi.nlm.nih.gov/pubmed/31882898 http://dx.doi.org/10.1038/s41598-019-56291-4 |
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