1887

Abstract

The neuraminidase inhibitor (NAI) oseltamivir is stockpiled globally as part of influenza pandemic preparedness. However, oseltamivir carboxylate (OC) resistance develops in avian influenza virus (AIV) infecting mallards exposed to environmental-like OC concentrations, suggesting that environmental resistance is a real concern. Herein we used an model to investigate if avian influenza H1N1 with the OC-resistant mutation NA-H274Y (51833/H274Y) as compared to the wild-type (wt) strain (51833 /wt) could transmit from mallards, which would potentially be exposed to environmentally contaminated environments, to and between chickens, thus posing a potential zoonotic risk of antiviral-resistant AIV. Regardless of whether the virus had the OC-resistant mutation or not, chickens became infected both through experimental infection, and following exposure to infected mallards. We found similar infection patterns between 51833/wt and 51833/H274Y such that, one chicken inoculated with 51833/wt and three chickens inoculated with 51833/H274Y were AIV positive in oropharyngeal samples more than 2 days consecutively, indicating true infection, and one contact chicken exposed to infected mallards was AIV positive in faecal samples for 3 consecutive days (51833/wt) and another contact chicken for 4 consecutive days (51833/H274Y). Importantly, all positive samples from chickens infected with 51833/H274Y retained the NA-H274Y mutation. However, none of the virus strains established sustained transmission in chickens, likely due to insufficient adaptation to the chicken host. Our results demonstrate that an OC-resistant avian influenza virus can transmit from mallards and replicate in chickens. NA-H274Y does not constitute a barrier to interspecies transmission per se, as the resistant virus did not show reduced replicative capacity compared to the wild-type counterpart. Thus, responsible use of oseltamivir and surveillance for resistance development is warranted to limit the risk of an OC-resistant pandemic strain.

Funding
This study was supported by the:
  • Family Olinder Nielsen's Foundation
    • Principle Award Recipient: SkogErik
  • Svenska Forskningsrådet Formas (Award 2016-00790)
    • Principle Award Recipient: D. JärhultJosef
  • Vetenskapsrådet (Award 2016-02606)
    • Principle Award Recipient: D. JärhultJosef
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2023-04-05
2024-10-03
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References

  1. Yen HL, Webster RG. Pandemic influenza as a current threat. Curr Top Microbiol Immunol 2009; 333:3–24 [View Article] [PubMed]
    [Google Scholar]
  2. Mostafa A, Abdelwhab EM, Mettenleiter TC, Pleschka S. Zoonotic potential of influenza A viruses: a comprehensive overview. Viruses 2018; 10:497 [View Article] [PubMed]
    [Google Scholar]
  3. Webster RG, Bean WJ, Gorman OT, Chambers TM, Kawaoka Y. Evolution and ecology of influenza A viruses. Microbiol Rev 1992; 56:152–179 [View Article] [PubMed]
    [Google Scholar]
  4. Vijaykrishna D, Mukerji R, Smith GJD. RNA virus reassortment: an evolutionary mechanism for host jumps and immune evasion. PLoS Pathog 2015; 11:e1004902 [View Article] [PubMed]
    [Google Scholar]
  5. Belshe RB. The origins of pandemic influenza-lessons from the 1918 virus. N Engl J Med 2005; 353:2209–2211 [View Article] [PubMed]
    [Google Scholar]
  6. Subbarao K. The critical interspecies transmission barrier at the animal⁻human interface. Trop Med Infect Dis 2019; 4:72 [View Article] [PubMed]
    [Google Scholar]
  7. Xu X, Subbarao K, Cox NJ, Guo Y. Genetic characterization of the pathogenic influenza A/Goose/Guangdong/1/96 (H5N1) virus: similarity of its hemagglutinin gene to those of H5N1 viruses from the 1997 outbreaks in Hong Kong. Virology 1999; 261:15–19 [View Article] [PubMed]
    [Google Scholar]
  8. de Jong JC, Claas EC, Osterhaus AD, Webster RG, Lim WL. A pandemic warning?. Nature 1997; 389:554 [View Article] [PubMed]
    [Google Scholar]
  9. Li KS, Guan Y, Wang J, Smith GJD, Xu KM et al. Genesis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia. Nature 2004; 430:209–213 [View Article] [PubMed]
    [Google Scholar]
  10. Alexander DJ. An overview of the epidemiology of avian influenza. Vaccine 2007; 25:5637–5644 [View Article] [PubMed]
    [Google Scholar]
  11. Tian H, Zhou S, Dong L, Van Boeckel TP, Cui Y et al. Avian influenza H5N1 viral and bird migration networks in Asia. Proc Natl Acad Sci 2015; 112:172–177 [View Article] [PubMed]
    [Google Scholar]
  12. Wang C, Wang J, Su W, Gao S, Luo J et al. Relationship between domestic and wild birds in live poultry market and a novel human H7N9 virus in China. J Infect Dis 2014; 209:34–37 [View Article] [PubMed]
    [Google Scholar]
  13. Zhou X, Li Y, Wang Y, Edwards J, Guo F et al. The role of live poultry movement and live bird market biosecurity in the epidemiology of influenza A (H7N9): A cross-sectional observational study in four eastern China provinces. J Infect 2015; 71:470–479 [View Article] [PubMed]
    [Google Scholar]
  14. Fan M, Huang B, Wang A, Deng L, Wu D et al. Human influenza A(H7N9) virus infection associated with poultry farm, Northeastern China. Emerg Infect Dis 2014; 20:1902–1905 [View Article] [PubMed]
    [Google Scholar]
  15. Wan Po AL, Farndon P, Palmer N. Maximizing the value of drug stockpiles for pandemic influenza. Emerg Infect Dis 2009; 15:1686–1687 [View Article] [PubMed]
    [Google Scholar]
  16. Hurt AC. The epidemiology and spread of drug resistant human influenza viruses. Curr Opin Virol 2014; 8:22–29 [View Article] [PubMed]
    [Google Scholar]
  17. Takashita E, Daniels RS, Fujisaki S, Gregory V, Gubareva LV et al. Global update on the susceptibilities of human influenza viruses to neuraminidase inhibitors and the cap-dependent endonuclease inhibitor baloxavir, 2017-2018. Antiviral Res 2020; 175:104718 [View Article] [PubMed]
    [Google Scholar]
  18. Marjuki H, Mishin VP, Chesnokov AP, De La Cruz JA, Davis CT et al. Neuraminidase mutations conferring resistance to oseltamivir in influenza A(H7N9) viruses. J Virol 2015; 89:5419–5426 [View Article] [PubMed]
    [Google Scholar]
  19. Kiso M, Iwatsuki-Horimoto K, Yamayoshi S, Uraki R, Ito M et al. Emergence of oseltamivir-resistant H7N9 influenza viruses in immunosuppressed cynomolgus macaques. J Infect Dis 2017; 216:582–593 [View Article] [PubMed]
    [Google Scholar]
  20. Govorkova EA, Ilyushina NA, Boltz DA, Douglas A, Yilmaz N et al. Efficacy of oseltamivir therapy in ferrets inoculated with different clades of H5N1 influenza virus. Antimicrob Agents Chemother 2007; 51:1414–1424 [View Article] [PubMed]
    [Google Scholar]
  21. Fick J, Lindberg RH, Tysklind M, Haemig PD, Waldenström J et al. Antiviral oseltamivir is not removed or degraded in normal sewage water treatment: implications for development of resistance by influenza A virus. PLoS One 2007; 2:e986 [View Article] [PubMed]
    [Google Scholar]
  22. Leknes H, Sturtzel IE, Dye C. Environmental release of oseltamivir from a Norwegian sewage treatment plant during the 2009 influenza A (H1N1) pandemic. Sci Total Environ 2012; 414:632–638 [View Article] [PubMed]
    [Google Scholar]
  23. He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet 1999; 37:471–484 [View Article] [PubMed]
    [Google Scholar]
  24. Gonçalves C, Pérez S, Osorio V, Petrovic M, Alpendurada MF et al. Photofate of oseltamivir (Tamiflu) and oseltamivir carboxylate under natural and simulated solar irradiation: kinetics, identification of the transformation products, and environmental occurrence. Environ Sci Technol 2011; 45:4307–4314 [View Article] [PubMed]
    [Google Scholar]
  25. Accinelli C, Saccà ML, Fick J, Mencarelli M, Lindberg R et al. Dissipation and removal of oseltamivir (Tamiflu) in different aquatic environments. Chemosphere 2010; 79:891–897 [View Article] [PubMed]
    [Google Scholar]
  26. Takanami R, Ozaki H, Giri RR, Taniguchi S, Hayashi S. Antiviral drugs zanamivir and oseltamivir found in wastewater and surface water in Osaka, Japan. J Wat Envir Tech 2012; 10:57–68 [View Article]
    [Google Scholar]
  27. Takanami R, Ozaki H, Giri RR, Taniguchi S, Hayashi S. Detection of antiviral drugs oseltamivir phosphate and oseltamivir carboxylate in Neya river, Osaka, Japan. J Wat Envir Tech 2010; 8:363–372 [View Article]
    [Google Scholar]
  28. Singer AC, Järhult JD, Grabic R, Khan GA, Lindberg RH et al. Intra- and inter-pandemic variations of antiviral, antibiotics and decongestants in wastewater treatment plants and receiving rivers. PLoS One 2014; 9:e108621 [View Article] [PubMed]
    [Google Scholar]
  29. Gillman A, Nykvist M, Muradrasoli S, Söderström H, Wille M et al. Influenza A(H7N9) virus acquires resistance-related neuraminidase I222T substitution when infected mallards are exposed to low levels of oseltamivir in water. Antimicrob Agents Chemother 2015; 59:5196–5202 [View Article] [PubMed]
    [Google Scholar]
  30. Gillman A, Muradrasoli S, Söderström H, Nordh J, Bröjer C et al. Resistance mutation R292K is induced in influenza A(H6N2) virus by exposure of infected mallards to low levels of oseltamivir. PLoS One 2013; 8:e71230 [View Article] [PubMed]
    [Google Scholar]
  31. Nykvist M, Gillman A, Söderström Lindström H, Tang C, Fedorova G et al. In vivo mallard experiments indicate that zanamivir has less potential for environmental influenza A virus resistance development than oseltamivir. J Gen Virol 2017; 98:2937–2949 [View Article] [PubMed]
    [Google Scholar]
  32. Tepper V, Nykvist M, Gillman A, Skog E, Wille M et al. Influenza A/H4N2 mallard infection experiments further indicate zanamivir as less prone to induce environmental resistance development than oseltamivir. J Gen Virol 2020; 101:816–824 [View Article] [PubMed]
    [Google Scholar]
  33. Achenbach JE, Bowen RA. Effect of oseltamivir carboxylate consumption on emergence of drug-resistant H5N2 avian influenza virus in Mallard ducks. Antimicrob Agents Chemother 2013; 57:2171–2181 [View Article] [PubMed]
    [Google Scholar]
  34. Järhult JD, Muradrasoli S, Wahlgren J, Söderström H, Orozovic G et al. Environmental levels of the antiviral oseltamivir induce development of resistance mutation H274Y in influenza A/H1N1 virus in mallards. PLoS One 2011; 6:e24742 [View Article] [PubMed]
    [Google Scholar]
  35. Gillman A, Muradrasoli S, Söderström H, Holmberg F, Latorre-Margalef N et al. Oseltamivir-resistant influenza A (H1N1) virus strain with an H274Y mutation in neuraminidase persists without drug pressure in infected mallards. Appl Environ Microbiol 2015; 81:2378–2383 [View Article] [PubMed]
    [Google Scholar]
  36. Olsen B, Munster VJ, Wallensten A, Waldenström J, Osterhaus ADME et al. Global patterns of influenza A virus in wild birds. Science 2006; 312:384–388 [View Article] [PubMed]
    [Google Scholar]
  37. Gilbert M, Xiao X, Robinson TP. Intensifying poultry production systems and the emergence of avian influenza in China: a “One Health/Ecohealth” epitome. Arch Public Health 2017; 75:48 [View Article] [PubMed]
    [Google Scholar]
  38. Yegani S, Shoushtari AH, Eshratabadi F, Molouki A. Full sequence analysis of hemagglutinin and neuraminidase genes and proteins of highly pathogenic avian influenza H5N1 virus detected in Iran, 2015. Trop Anim Health Prod 2019; 51:605–612 [View Article] [PubMed]
    [Google Scholar]
  39. Söderström H, Järhult JD, Olsen B, Lindberg RH, Tanaka H et al. Detection of the antiviral drug oseltamivir in aquatic environments. PLoS One 2009; 4:e6064 [View Article] [PubMed]
    [Google Scholar]
  40. Bialy D, Shelton H. Functional neuraminidase inhibitor resistance motifs in avian influenza A(H5Nx) viruses. Antiviral Res 2020; 182:104886 [View Article] [PubMed]
    [Google Scholar]
  41. Latorre-Margalef N, Tolf C, Grosbois V, Avril A, Bengtsson D et al. Long-term variation in influenza A virus prevalence and subtype diversity in migratory mallards in northern Europe. Proc Biol Sci 2014; 281:20140098 [View Article] [PubMed]
    [Google Scholar]
  42. Reed LJ, Muench H. A simple method of estimating fifty percent endpoints. Am J Hyg 1938; 27:493–497 [View Article]
    [Google Scholar]
  43. Pantin-Jackwood MJ, Swayne DE. Pathogenesis and pathobiology of avian influenza virus infection in birds. Rev Sci Tech 2009; 28:113–136 [PubMed]
    [Google Scholar]
  44. Spackman E, Suarez DL. Type A influenza virus detection and quantitation by real-time RT-PCR. Methods Mol Biol 2008; 436:19–26 [View Article] [PubMed]
    [Google Scholar]
  45. Lackenby A. Respiratory virus unit HPA. influenza MUNANA neuraminidase activity and inhibition assay (flourescent IC50 assay) SOP no V-6815/01-10. n.d
  46. Lackenby A. Respiratory Virus Unit HPA. n.d www.isirv.org/site/index.php/methodology/nai-assay-ic50
  47. Bröjer C, Agren EO, Uhlhorn H, Bernodt K, Mörner T et al. Pathology of natural highly pathogenic avian influenza H5N1 infection in wild tufted ducks (Aythya fuligula). J Vet Diagn Invest 2009; 21:579–587 [View Article] [PubMed]
    [Google Scholar]
  48. Bergervoet SA, Germeraad EA, Alders M, Roose MM, Engelsma MY et al. Susceptibility of chickens to low pathogenic avian influenza (LPAI) viruses of wild bird- and poultry-associated subtypes. Viruses 2019; 11:1010 [View Article] [PubMed]
    [Google Scholar]
  49. Wille M, Bröjer C, Lundkvist Å, Järhult JD. Alternate routes of influenza A virus infection in Mallard (Anas platyrhynchos). Vet Res 2018; 49:110 [View Article] [PubMed]
    [Google Scholar]
  50. Swayne DE, Slemons RD. Comparative pathology of a chicken-origin and two duck-origin influenza virus isolates in chickens: the effect of route of inoculation. Vet Pathol 1994; 31:237–245 [View Article] [PubMed]
    [Google Scholar]
  51. Starick E, Fereidouni SR, Lange E, Grund C, Vahlenkamp T et al. Analysis of influenza A viruses of subtype H1 from wild birds, turkeys and pigs in Germany reveals interspecies transmission events. Influenza Other Respir Viruses 2011; 5:276–284 [View Article] [PubMed]
    [Google Scholar]
  52. Moscona A. Global transmission of oseltamivir-resistant influenza. N Engl J Med 2009; 360:953–956 [View Article] [PubMed]
    [Google Scholar]
  53. Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R et al. Avian influenza A (H5N1) infection in humans. N Engl J Med 2005; 353:1374–1385 [View Article] [PubMed]
    [Google Scholar]
  54. de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJD et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med 2005; 353:2667–2672 [View Article] [PubMed]
    [Google Scholar]
  55. Taubenberger JK, Kash JC. Influenza virus evolution, host adaptation, and pandemic formation. Cell Host Microbe 2010; 7:440–451 [View Article] [PubMed]
    [Google Scholar]
  56. de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ et al. Human cases of influenza at the human-animal interface, January 2015–April 2017. Wkly Epidemiol Rec 2017; 92:460–475 [View Article] [PubMed]
    [Google Scholar]
  57. Nguyen-Van-Tam JS, Openshaw PJM, Nicholson KG. Antivirals for influenza: where now for clinical practice and pandemic preparedness?. Lancet 2014; 384:386–387 [View Article] [PubMed]
    [Google Scholar]
  58. Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med 2018; 379:913–923 [View Article] [PubMed]
    [Google Scholar]
  59. Uehara T, Hayden FG, Kawaguchi K, Omoto S, Hurt AC et al. Treatment-emergent influenza variant viruses with reduced baloxavir susceptibility: impact on clinical and virologic outcomes in uncomplicated influenza. J Infect Dis 2020; 221:346–355 [View Article] [PubMed]
    [Google Scholar]
  60. Omoto S, Speranzini V, Hashimoto T, Noshi T, Yamaguchi H et al. Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Sci Rep 2018; 8:9633 [View Article] [PubMed]
    [Google Scholar]
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