Influenza is a persistent threat to human health and there is a continuing requirement for updating anti-influenza strategies. Initiated by observations of different endoplasmic reticulum (ER) responses of host to seasonal H1N1 and highly pathogenic avian influenza (HPAI) A H5N1 infections, we identified an alternative antiviral role of tauroursodeoxycholic acid (TUDCA), a clinically available ER stress inhibitor, both in vitro and in vivo. Rather than modulating ER stress in host cells, TUDCA abolished the proton conductivity of viral M2 by disrupting its oligomeric states, which induces inefficient viral infection. We also showed that M2 penetrated cells, whose intracellular uptake depended on its proton channel activity, an effect observed in both TUDCA and M2 inhibitor amantadine. The identification and application of TUDCA as an inhibitor of M2 proton channel will expand our understanding of IAV biology and complement current anti-IAV arsenals.

中文翻译：

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牛磺熊去氧胆酸 (TUDCA) 通过破坏病毒质子通道 M2 来抑制甲型流感病毒感染。

流感是对人类健康的持续威胁，因此需要不断更新抗流感策略。通过观察宿主对季节性 H1N1 和高致病性禽流感 (HPAI) A H5N1 感染的不同内质网 (ER) 反应，我们确定了牛磺熊去氧胆酸 (TUDCA) 的另一种抗病毒作用，这是一种临床上可用的 ER 应激抑制剂，无论是在体外和体内。TUDCA 不是调节宿主细胞中的 ER 应激，而是通过破坏其寡聚状态来消除病毒 M2 的质子传导性，从而导致低效的病毒感染。我们还表明 M2 穿透细胞，其细胞内摄取取决于其质子通道活性，这是在 TUDCA 和 M2 抑制剂金刚烷胺中观察到的效果。