Cargando…
Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure
BACKGROUND: Wild waterfowl is the natural reservoir of influenza A virus (IAV); hosted viruses are very variable and provide a source for genetic segments which can reassort with poultry or mammalian adapted IAVs to generate novel species crossing viruses. Additionally, wild waterfowl act as a reser...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589409/ https://www.ncbi.nlm.nih.gov/pubmed/26422258 http://dx.doi.org/10.1371/journal.pone.0139415 |
_version_ | 1782392788631945216 |
---|---|
author | Gillman, Anna Muradrasoli, Shaman Mårdnäs, Andreas Söderström, Hanna Fedorova, Ganna Löwenthal, Max Wille, Michelle Daggfeldt, Annika Järhult, Josef D. |
author_facet | Gillman, Anna Muradrasoli, Shaman Mårdnäs, Andreas Söderström, Hanna Fedorova, Ganna Löwenthal, Max Wille, Michelle Daggfeldt, Annika Järhult, Josef D. |
author_sort | Gillman, Anna |
collection | PubMed |
description | BACKGROUND: Wild waterfowl is the natural reservoir of influenza A virus (IAV); hosted viruses are very variable and provide a source for genetic segments which can reassort with poultry or mammalian adapted IAVs to generate novel species crossing viruses. Additionally, wild waterfowl act as a reservoir for highly pathogenic IAVs. Exposure of wild birds to the antiviral drug oseltamivir may occur in the environment as its active metabolite can be released from sewage treatment plants to river water. Resistance to oseltamivir, or to other neuraminidase inhibitors (NAIs), in IAVs of wild waterfowl has not been extensively studied. AIM AND METHODS: In a previous in vivo Mallard experiment, an influenza A(H6N2) virus developed oseltamivir resistance by the R292K substitution in the neuraminidase (NA), when the birds were exposed to oseltamivir. In this study we tested if the resistance could be maintained in Mallards without drug exposure. Three variants of resistant H6N2/R292K virus were each propagated during 17 days in five successive pairs of naïve Mallards, while oseltamivir exposure was decreased and removed. Daily fecal samples were analyzed for viral presence, genotype and phenotype. RESULTS AND CONCLUSION: Within three days without drug exposure no resistant viruses could be detected by NA sequencing, which was confirmed by functional NAI sensitivity testing. We conclude that this resistant N2 virus could not compete in fitness with wild type subpopulations without oseltamivir drug pressure, and thus has no potential to circulate among wild birds. The results of this study contrast to previous observations of drug induced resistance in an avian H1N1 virus, which was maintained also without drug exposure in Mallards. Experimental observations on persistence of NAI resistance in avian IAVs resemble NAI resistance seen in human IAVs, in which resistant N2 subtypes do not circulate, while N1 subtypes with permissive mutations can circulate without drug pressure. We speculate that the phylogenetic group N1 NAs may easier compensate for NAI resistance than group N2 NAs, though further studies are needed to confirm such conclusions. |
format | Online Article Text |
id | pubmed-4589409 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-45894092015-10-02 Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure Gillman, Anna Muradrasoli, Shaman Mårdnäs, Andreas Söderström, Hanna Fedorova, Ganna Löwenthal, Max Wille, Michelle Daggfeldt, Annika Järhult, Josef D. PLoS One Research Article BACKGROUND: Wild waterfowl is the natural reservoir of influenza A virus (IAV); hosted viruses are very variable and provide a source for genetic segments which can reassort with poultry or mammalian adapted IAVs to generate novel species crossing viruses. Additionally, wild waterfowl act as a reservoir for highly pathogenic IAVs. Exposure of wild birds to the antiviral drug oseltamivir may occur in the environment as its active metabolite can be released from sewage treatment plants to river water. Resistance to oseltamivir, or to other neuraminidase inhibitors (NAIs), in IAVs of wild waterfowl has not been extensively studied. AIM AND METHODS: In a previous in vivo Mallard experiment, an influenza A(H6N2) virus developed oseltamivir resistance by the R292K substitution in the neuraminidase (NA), when the birds were exposed to oseltamivir. In this study we tested if the resistance could be maintained in Mallards without drug exposure. Three variants of resistant H6N2/R292K virus were each propagated during 17 days in five successive pairs of naïve Mallards, while oseltamivir exposure was decreased and removed. Daily fecal samples were analyzed for viral presence, genotype and phenotype. RESULTS AND CONCLUSION: Within three days without drug exposure no resistant viruses could be detected by NA sequencing, which was confirmed by functional NAI sensitivity testing. We conclude that this resistant N2 virus could not compete in fitness with wild type subpopulations without oseltamivir drug pressure, and thus has no potential to circulate among wild birds. The results of this study contrast to previous observations of drug induced resistance in an avian H1N1 virus, which was maintained also without drug exposure in Mallards. Experimental observations on persistence of NAI resistance in avian IAVs resemble NAI resistance seen in human IAVs, in which resistant N2 subtypes do not circulate, while N1 subtypes with permissive mutations can circulate without drug pressure. We speculate that the phylogenetic group N1 NAs may easier compensate for NAI resistance than group N2 NAs, though further studies are needed to confirm such conclusions. Public Library of Science 2015-09-30 /pmc/articles/PMC4589409/ /pubmed/26422258 http://dx.doi.org/10.1371/journal.pone.0139415 Text en © 2015 Gillman 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 Gillman, Anna Muradrasoli, Shaman Mårdnäs, Andreas Söderström, Hanna Fedorova, Ganna Löwenthal, Max Wille, Michelle Daggfeldt, Annika Järhult, Josef D. Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure |
title | Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure |
title_full | Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure |
title_fullStr | Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure |
title_full_unstemmed | Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure |
title_short | Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure |
title_sort | oseltamivir resistance in influenza a(h6n2) caused by an r292k substitution in neuraminidase is not maintained in mallards without drug pressure |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589409/ https://www.ncbi.nlm.nih.gov/pubmed/26422258 http://dx.doi.org/10.1371/journal.pone.0139415 |
work_keys_str_mv | AT gillmananna oseltamivirresistanceininfluenzaah6n2causedbyanr292ksubstitutioninneuraminidaseisnotmaintainedinmallardswithoutdrugpressure AT muradrasolishaman oseltamivirresistanceininfluenzaah6n2causedbyanr292ksubstitutioninneuraminidaseisnotmaintainedinmallardswithoutdrugpressure AT mardnasandreas oseltamivirresistanceininfluenzaah6n2causedbyanr292ksubstitutioninneuraminidaseisnotmaintainedinmallardswithoutdrugpressure AT soderstromhanna oseltamivirresistanceininfluenzaah6n2causedbyanr292ksubstitutioninneuraminidaseisnotmaintainedinmallardswithoutdrugpressure AT fedorovaganna oseltamivirresistanceininfluenzaah6n2causedbyanr292ksubstitutioninneuraminidaseisnotmaintainedinmallardswithoutdrugpressure AT lowenthalmax oseltamivirresistanceininfluenzaah6n2causedbyanr292ksubstitutioninneuraminidaseisnotmaintainedinmallardswithoutdrugpressure AT willemichelle oseltamivirresistanceininfluenzaah6n2causedbyanr292ksubstitutioninneuraminidaseisnotmaintainedinmallardswithoutdrugpressure AT daggfeldtannika oseltamivirresistanceininfluenzaah6n2causedbyanr292ksubstitutioninneuraminidaseisnotmaintainedinmallardswithoutdrugpressure AT jarhultjosefd oseltamivirresistanceininfluenzaah6n2causedbyanr292ksubstitutioninneuraminidaseisnotmaintainedinmallardswithoutdrugpressure |