Gillman Anna, Muradrasoli Shaman, Söderström Hanna, Holmberg Fredrik, Latorre-Margalef Neus, Tolf Conny, Waldenström Jonas, Gunnarsson Gunnar, Olsen Björn, Järhult Josef D
Section for Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden Zoonosis Science Centre, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden
Zoonosis Science Centre, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala, Sweden.
Appl Environ Microbiol. 2015 Apr;81(7):2378-83. doi: 10.1128/AEM.04034-14. Epub 2015 Jan 23.
Influenza A virus (IAV) has its natural reservoir in wild waterfowl, and emerging human IAVs often contain gene segments from avian viruses. The active drug metabolite of oseltamivir (oseltamivir carboxylate [OC]), stockpiled as Tamiflu for influenza pandemic preparedness, is not removed by conventional sewage treatment and has been detected in river water. There, it may exert evolutionary pressure on avian IAV in waterfowl, resulting in the development of resistant viral variants. A resistant avian IAV can circulate among wild birds only if resistance does not restrict viral fitness and if the resistant virus can persist without continuous drug pressure. In this in vivo mallard (Anas platyrhynchos) study, we tested whether an OC-resistant avian IAV (H1N1) strain with an H274Y mutation in the neuraminidase (NA-H274Y) could retain resistance while drug pressure was gradually removed. Successively infected mallards were exposed to decreasing levels of OC, and fecal samples were analyzed for the neuraminidase sequence and phenotypic resistance. No reversion to wild-type virus was observed during the experiment, which included 17 days of viral transmission among 10 ducks exposed to OC concentrations below resistance induction levels. We conclude that resistance in avian IAV that is induced by exposure of the natural host to OC can persist in the absence of the drug. Thus, there is a risk that human-pathogenic IAVs that evolve from IAVs circulating among wild birds may contain resistance mutations. An oseltamivir-resistant pandemic IAV would pose a substantial public health threat. Therefore, our observations underscore the need for prudent oseltamivir use, upgraded sewage treatment, and surveillance for resistant IAVs in wild birds.
甲型流感病毒（IAV）在野生水禽中存在天然宿主，新出现的人类IAV通常包含来自禽病毒的基因片段。作为流感大流行防范储备药物的奥司他韦的活性药物代谢产物（奥司他韦羧酸盐[OC]），无法通过传统污水处理去除，且已在河水中检测到。在那里，它可能对水禽中的禽IAV施加进化压力，导致耐药病毒变体的出现。只有当耐药性不限制病毒适应性且耐药病毒能够在没有持续药物压力的情况下持续存在时，耐药禽IAV才能在野生鸟类中传播。在这项针对绿头鸭（Anas platyrhynchos）的体内研究中，我们测试了一种在神经氨酸酶中具有H274Y突变的OC耐药禽IAV（H1N1）毒株在逐渐去除药物压力时是否能够保持耐药性。连续感染的绿头鸭暴露于逐渐降低水平的OC中，并对粪便样本进行神经氨酸酶序列和表型耐药性分析。在实验过程中未观察到向野生型病毒的逆转，该实验包括在10只暴露于低于耐药诱导水平的OC浓度的鸭子之间进行17天的病毒传播。我们得出结论，天然宿主暴露于OC诱导的禽IAV耐药性在没有药物的情况下可以持续存在。因此，从野生鸟类中传播的IAV进化而来的人类致病性IAV可能含有耐药突变，存在这样的风险。对奥司他韦耐药的大流行IAV将对公众健康构成重大威胁。因此，我们的观察结果强调了谨慎使用奥司他韦、升级污水处理以及监测野生鸟类中耐药IAV的必要性。
