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Multidrug Resistant 2009 A/H1N1 Influenza Clinical Isolate with a Neuraminidase I223R Mutation Retains Its Virulence and Transmissibility in Ferrets


Only two classes of antiviral drugs, neuraminidase inhibitors and adamantanes, are approved for prophylaxis and therapy against influenza virus infections. A major concern is that influenza virus becomes resistant to these antiviral drugs and spreads in the human population. The 2009 pandemic A/H1N1 influenza virus is naturally resistant to adamantanes. Recently a novel neuraminidase I223R mutation was identified in an A/H1N1 virus showing cross-resistance to the neuraminidase inhibitors oseltamivir, zanamivir and peramivir. However, the ability of this virus to cause disease and spread in the human population is unknown. Therefore, this clinical isolate (NL/2631-R223) was compared with a well-characterized reference virus (NL/602). In vitro experiments showed that NL/2631-I223R replicated as well as NL/602 in MDCK cells. In a ferret pathogenesis model, body weight loss was similar in animals inoculated with NL/2631-R223 or NL/602. In addition, pulmonary lesions were similar at day 4 post inoculation. However, at day 7 post inoculation, NL/2631-R223 caused milder pulmonary lesions and degree of alveolitis than NL/602. This indicated that the mutant virus was less pathogenic. Both NL/2631-R223 and a recombinant virus with a single I223R change (recNL/602-I223R), transmitted among ferrets by aerosols, despite observed attenuation of recNL/602-I223R in vitro. In conclusion, the I223R mutated virus isolate has comparable replicative ability and transmissibility, but lower pathogenicity than the reference virus based on these in vivo studies. This implies that the 2009 pandemic influenza A/H1N1 virus subtype with an isoleucine to arginine change at position 223 in the neuraminidase has the potential to spread in the human population. It is important to be vigilant for this mutation in influenza surveillance and to continue efforts to increase the arsenal of antiviral drugs to combat influenza.


Vyšlo v časopise: Multidrug Resistant 2009 A/H1N1 Influenza Clinical Isolate with a Neuraminidase I223R Mutation Retains Its Virulence and Transmissibility in Ferrets. PLoS Pathog 7(9): e32767. doi:10.1371/journal.ppat.1002276
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002276

Souhrn

Only two classes of antiviral drugs, neuraminidase inhibitors and adamantanes, are approved for prophylaxis and therapy against influenza virus infections. A major concern is that influenza virus becomes resistant to these antiviral drugs and spreads in the human population. The 2009 pandemic A/H1N1 influenza virus is naturally resistant to adamantanes. Recently a novel neuraminidase I223R mutation was identified in an A/H1N1 virus showing cross-resistance to the neuraminidase inhibitors oseltamivir, zanamivir and peramivir. However, the ability of this virus to cause disease and spread in the human population is unknown. Therefore, this clinical isolate (NL/2631-R223) was compared with a well-characterized reference virus (NL/602). In vitro experiments showed that NL/2631-I223R replicated as well as NL/602 in MDCK cells. In a ferret pathogenesis model, body weight loss was similar in animals inoculated with NL/2631-R223 or NL/602. In addition, pulmonary lesions were similar at day 4 post inoculation. However, at day 7 post inoculation, NL/2631-R223 caused milder pulmonary lesions and degree of alveolitis than NL/602. This indicated that the mutant virus was less pathogenic. Both NL/2631-R223 and a recombinant virus with a single I223R change (recNL/602-I223R), transmitted among ferrets by aerosols, despite observed attenuation of recNL/602-I223R in vitro. In conclusion, the I223R mutated virus isolate has comparable replicative ability and transmissibility, but lower pathogenicity than the reference virus based on these in vivo studies. This implies that the 2009 pandemic influenza A/H1N1 virus subtype with an isoleucine to arginine change at position 223 in the neuraminidase has the potential to spread in the human population. It is important to be vigilant for this mutation in influenza surveillance and to continue efforts to increase the arsenal of antiviral drugs to combat influenza.


Zdroje

1. MontoAS 2003 The role of antivirals in the control of influenza. Vaccine 21 1796 1800

2. BautistaEChotpitayasunondhTGaoZHarperSAShawM 2010 Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med 362 1708 1719

3. LeeVJYapJCookARChenMITayJK 2010 Oseltamivir ring prophylaxis for containment of 2009 H1N1 influenza outbreaks. N Engl J Med 362 2166 2174

4. Dominguez-CheritGLapinskySEMaciasAEPintoREspinosa-PerezL 2009 Critically Ill patients with 2009 influenza A(H1N1) in Mexico. JAMA 302 1880 1887

5. WHO 2011 Update on oseltamivir resistance to influenza H1N1 (2009) viruses. Geneva World Health Organisation http://www.who.int/csr/disease/influenza/2011_07_15_weekly_web_update_oseltamivir_resistance.pdf

6. HarvalaHGunsonRSimmondsPHardieABennettS 2010 The emergence of oseltamivir-resistant pandemic influenza A (H1N1) 2009 virus amongst hospitalised immunocompromised patients in Scotland, November-December, 2009. Euro Surveill 15pii: 19536

7. GaurAHBaggaBBarmanSHaydenRLampteyA 2010 Intravenous zanamivir for oseltamivir-resistant 2009 H1N1 influenza. N Engl J Med 362 88 89

8. MontoASMcKimm-BreschkinJLMackenCHampsonAWHayA 2006 Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use. Antimicrob Agents Chemother 50 2395 2402

9. KisoMMitamuraKSakai-TagawaYShiraishiKKawakamiC 2004 Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 364 759 765

10. HaugeSHDudmanSBorgenKLackenbyAHungnesO 2009 Oseltamivir-resistant influenza viruses A (H1N1), Norway, 2007-08. Emerg Infect Dis 15 155 162

11. MeijerALackenbyAHungnesOLinaBvan-der-WerfS 2009 Oseltamivir-resistant influenza virus A (H1N1), Europe, 2007-08 season. Emerg Infect Dis 15 552 560

12. IvesJACarrJAMendelDBTaiCYLambkinR 2002 The H274Y mutation in the influenza A/H1N1 neuraminidase active site following oseltamivir phosphate treatment leave virus severely compromised both in vitro and in vivo. Antiviral Res 55 307 317

13. HerlocherMLCarrJIvesJEliasSTrusconR 2002 Influenza virus carrying an R292K mutation in the neuraminidase gene is not transmitted in ferrets. Antiviral Res 54 99 111

14. CarrJIvesJKellyLLambkinROxfordJ 2002 Influenza virus carrying neuraminidase with reduced sensitivity to oseltamivir carboxylate has altered properties in vitro and is compromised for infectivity and replicative ability in vivo. Antiviral Res 54 79 88

15. van der VriesEvan den BergBSchuttenM 2008 Fatal oseltamivir-resistant influenza virus infection. N Engl J Med 359 1074 1076

16. BazMAbedYSimonPHamelinMEBoivinG 2010 Effect of the neuraminidase mutation H274Y conferring resistance to oseltamivir on the replicative capacity and virulence of old and recent human influenza A(H1N1) viruses. J Infect Dis 201 740 745

17. BouvierNMLowenACPaleseP 2008 Oseltamivir-resistant influenza A viruses are transmitted efficiently among guinea pigs by direct contact but not by aerosol. J Virol 82 10052 10058

18. BloomJDGongLIBaltimoreD 2010 Permissive secondary mutations enable the evolution of influenza oseltamivir resistance. Science 328 1272 1275

19. CollinsPJHaireLFLinYPLiuJRussellRJ 2009 Structural basis for oseltamivir resistance of influenza viruses. Vaccine 27 6317 6323

20. DuanSBoltzDASeilerPLiJBragstadK 2010 Oseltamivir-resistant pandemic H1N1/2009 influenza virus possesses lower transmissibility and fitness in ferrets. PLoS Pathog 6 e1001022

21. HamelinMEBazMAbedYCoutureCJoubertP 2010 Oseltamivir-resistant pandemic A/H1N1 virus is as virulent as its wild-type counterpart in mice and ferrets. PLoS Pathog 6 e1001015

22. KisoMShinyaKShimojimaMTakanoRTakahashiK 2010 Characterization of oseltamivir-resistant 2009 H1N1 pandemic influenza A viruses. PLoS Pathog 6 e1001079

23. MemoliMJDavisASProudfootKChertowDSHrabalRJ 2011 Multidrug-resistant 2009 pandemic influenza A(H1N1) viruses maintain fitness and transmissibility in ferrets. J Infect Dis 203 348 357

24. SeibertCWKaminskiMPhilippJRubbenstrothDAlbrechtRA 2010 Oseltamivir-resistant variants of the 2009 pandemic H1N1 influenza A virus are not attenuated in the guinea pig and ferret transmission models. J Virol 84 11219 11226

25. van der VriesEStelmaFFBoucherCA 2010 Emergence of a multidrug-resistant pandemic influenza A (H1N1) virus. N Engl J Med 363 1381 1382

26. NguyenHTFryAMLovelessPAKlimovAIGubarevaLV 2010 Recovery of a multidrug-resistant strain of pandemic influenza A 2009 (H1N1) virus carrying a dual H275Y/I223R mutation from a child after prolonged treatment with oseltamivir. Clin Infect Dis 51 983 984

27. MunsterVJde WitEvan den BrandJMHerfstSSchrauwenEJ 2009 Pathogenesis and transmission of swine-origin 2009 A(H1N1) influenza virus in ferrets. Science 325 481 483

28. SquiresBMackenCGarcia-SastreAGodboleSNoronhaJ 2008 BioHealthBase: informatics support in the elucidation of influenza virus host pathogen interactions and virulence. Nucleic Acids Res 36 D497 503

29. van den BrandJMStittelaarKJvan AmerongenGRimmelzwaanGFSimonJ 2010 Severity of pneumonia due to new H1N1 influenza virus in ferrets is intermediate between that due to seasonal H1N1 virus and highly pathogenic avian influenza H5N1 virus. J Infect Dis 201 993 999

30. Centers for Disease C, Prevention 2009 Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis--North Carolina, 2009. MMWR Morb Mortal Wkly Rep 58 969 972

31. HurtALeeRLeangSCuiLDengY 2011 Increased detection in Australia and Singapore of a novel influenza A(H1N1)2009 variant with reduced oseltamivir and zanamivir sensitivity due to a S247N neuraminidase mutation. Euro Surveill 16 pii: 19884

32. HerfstSChutinimitkulSYeJde WitEMunsterVJ 2010 Introduction of virulence markers in PB2 of pandemic swine-origin influenza virus does not result in enhanced virulence or transmission. J Virol 84 3752 3758

33. McCawJMArinaminpathyNHurtACMcVernonJMcLeanAR 2011 A mathematical framework for estimating pathogen transmission fitness and inoculum size using data from a competitive mixtures animal model. PLoS Comput Biol 7 e1002026

34. SchrauwenEJHerfstSChutinimitkulSBestebroerTMRimmelzwaanGF 2011 Possible increased pathogenicity of pandemic (H1N1) 2009 influenza virus upon reassortment. Emerg Infect Dis 17 200 208

35. MatrosovichMMatrosovichTCarrJRobertsNAKlenkHD 2003 Overexpression of the alpha-2,6-sialyltransferase in MDCK cells increases influenza virus sensitivity to neuraminidase inhibitors. J Virol 77 8418 8425

36. de WitESpronkenMIBestebroerTMRimmelzwaanGFOsterhausAD 2004 Efficient generation and growth of influenza virus A/PR/8/34 from eight cDNA fragments. Virus Res 103 155 161

37. KarberG 1931 Beitrag zur kollektiven behandlung pharmakologischer reihenversuche. Exp Pathol Pharmakol 162 480 483

38. FouchierRABestebroerTMHerfstSVan Der KempLRimmelzwaanGF 2000 Detection of influenza A viruses from different species by PCR amplification of conserved sequences in the matrix gene. J Clin Microbiol 38 4096 4101

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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