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Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards
Oseltamivir (Tamiflu®) is the most widely used drug against influenza infections and is extensively stockpiled worldwide as part of pandemic preparedness plans. However, resistance is a growing problem and in 2008–2009, seasonal human influenza A/H1N1 virus strains in most parts of the world carried...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171471/ https://www.ncbi.nlm.nih.gov/pubmed/21931841 http://dx.doi.org/10.1371/journal.pone.0024742 |
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author | Järhult, Josef D. Muradrasoli, Shaman Wahlgren, John Söderström, Hanna Orozovic, Goran Gunnarsson, Gunnar Bröjer, Caroline Latorre-Margalef, Neus Fick, Jerker Grabic, Roman Lennerstrand, Johan Waldenström, Jonas Lundkvist, Åke Olsen, Björn |
author_facet | Järhult, Josef D. Muradrasoli, Shaman Wahlgren, John Söderström, Hanna Orozovic, Goran Gunnarsson, Gunnar Bröjer, Caroline Latorre-Margalef, Neus Fick, Jerker Grabic, Roman Lennerstrand, Johan Waldenström, Jonas Lundkvist, Åke Olsen, Björn |
author_sort | Järhult, Josef D. |
collection | PubMed |
description | Oseltamivir (Tamiflu®) is the most widely used drug against influenza infections and is extensively stockpiled worldwide as part of pandemic preparedness plans. However, resistance is a growing problem and in 2008–2009, seasonal human influenza A/H1N1 virus strains in most parts of the world carried the mutation H274Y in the neuraminidase gene which causes resistance to the drug. The active metabolite of oseltamivir, oseltamivir carboxylate (OC), is poorly degraded in sewage treatment plants and surface water and has been detected in aquatic environments where the natural influenza reservoir, dabbling ducks, can be exposed to the substance. To assess if resistance can develop under these circumstances, we infected mallards with influenza A/H1N1 virus and exposed the birds to 80 ng/L, 1 µg/L and 80 µg/L of OC through their sole water source. By sequencing the neuraminidase gene from fecal samples, we found that H274Y occurred at 1 µg/L of OC and rapidly dominated the viral population at 80 µg/L. IC(50) for OC was increased from 2–4 nM in wild-type viruses to 400–700 nM in H274Y mutants as measured by a neuraminidase inhibition assay. This is consistent with the decrease in sensitivity to OC that has been noted among human clinical isolates carrying H274Y. Environmental OC levels have been measured to 58–293 ng/L during seasonal outbreaks and are expected to reach µg/L-levels during pandemics. Thus, resistance could be induced in influenza viruses circulating among wild ducks. As influenza viruses can cross species barriers, oseltamivir resistance could spread to human-adapted strains with pandemic potential disabling oseltamivir, a cornerstone in pandemic preparedness planning. We propose surveillance in wild birds as a measure to understand the resistance situation in nature and to monitor it over time. Strategies to lower environmental levels of OC include improved sewage treatment and, more importantly, a prudent use of antivirals. |
format | Online Article Text |
id | pubmed-3171471 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-31714712011-09-19 Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards Järhult, Josef D. Muradrasoli, Shaman Wahlgren, John Söderström, Hanna Orozovic, Goran Gunnarsson, Gunnar Bröjer, Caroline Latorre-Margalef, Neus Fick, Jerker Grabic, Roman Lennerstrand, Johan Waldenström, Jonas Lundkvist, Åke Olsen, Björn PLoS One Research Article Oseltamivir (Tamiflu®) is the most widely used drug against influenza infections and is extensively stockpiled worldwide as part of pandemic preparedness plans. However, resistance is a growing problem and in 2008–2009, seasonal human influenza A/H1N1 virus strains in most parts of the world carried the mutation H274Y in the neuraminidase gene which causes resistance to the drug. The active metabolite of oseltamivir, oseltamivir carboxylate (OC), is poorly degraded in sewage treatment plants and surface water and has been detected in aquatic environments where the natural influenza reservoir, dabbling ducks, can be exposed to the substance. To assess if resistance can develop under these circumstances, we infected mallards with influenza A/H1N1 virus and exposed the birds to 80 ng/L, 1 µg/L and 80 µg/L of OC through their sole water source. By sequencing the neuraminidase gene from fecal samples, we found that H274Y occurred at 1 µg/L of OC and rapidly dominated the viral population at 80 µg/L. IC(50) for OC was increased from 2–4 nM in wild-type viruses to 400–700 nM in H274Y mutants as measured by a neuraminidase inhibition assay. This is consistent with the decrease in sensitivity to OC that has been noted among human clinical isolates carrying H274Y. Environmental OC levels have been measured to 58–293 ng/L during seasonal outbreaks and are expected to reach µg/L-levels during pandemics. Thus, resistance could be induced in influenza viruses circulating among wild ducks. As influenza viruses can cross species barriers, oseltamivir resistance could spread to human-adapted strains with pandemic potential disabling oseltamivir, a cornerstone in pandemic preparedness planning. We propose surveillance in wild birds as a measure to understand the resistance situation in nature and to monitor it over time. Strategies to lower environmental levels of OC include improved sewage treatment and, more importantly, a prudent use of antivirals. Public Library of Science 2011-09-12 /pmc/articles/PMC3171471/ /pubmed/21931841 http://dx.doi.org/10.1371/journal.pone.0024742 Text en Järhult 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 Järhult, Josef D. Muradrasoli, Shaman Wahlgren, John Söderström, Hanna Orozovic, Goran Gunnarsson, Gunnar Bröjer, Caroline Latorre-Margalef, Neus Fick, Jerker Grabic, Roman Lennerstrand, Johan Waldenström, Jonas Lundkvist, Åke Olsen, Björn Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards |
title | Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards |
title_full | Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards |
title_fullStr | Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards |
title_full_unstemmed | Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards |
title_short | Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards |
title_sort | environmental levels of the antiviral oseltamivir induce development of resistance mutation h274y in influenza a/h1n1 virus in mallards |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3171471/ https://www.ncbi.nlm.nih.gov/pubmed/21931841 http://dx.doi.org/10.1371/journal.pone.0024742 |
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