Influenza A(H7N9) Virus Acquires Resistance-Related Neuraminidase I222T Substitution When Infected Mallards Are Exposed to Low Levels of Oseltamivir in Water

摘要: Influenza A virus (IAV) has its natural reservoir in wild waterfowl, and new human IAVs often contain gene segments originating from avian IAVs. Treatment options for severe influenza are principally restricted to neuraminidase inhibitors (NAIs), among which oseltamivir is stockpiled preparedness pandemics. There evolutionary pressure the environment resistance development IAVs, as active metabolite carboxylate (OC) passes largely undegraded through sewage treatment river water where waterfowl reside. In an vivo mallard (Anas platyrhynchos) model, we tested if low-pathogenic A(H7N9) might become resistant host was exposed low levels of OC. Ducks were experimentally infected, OC added their water, after infection transmission maintained by successive introductions uninfected birds. Daily fecal samples IAV excretion, genotype, phenotype. Following exposure 2.5 μg/liter OC, resistance-related (NA) I222T substitution, detected within 2 days during first passage found all viruses sequenced subsequently introduced ducks. The substitution generated 8-fold 2.4-fold increases 50% inhibitory concentration (IC50) (P < 0.001) zanamivir = 0.016), respectively. We conclude that hosts, same magnitude environment, may result amino acid substitutions, leading changed antiviral sensitivity subtype can be highly pathogenic humans. Prudent use surveillance birds warranted.