Dexamethasone disrupts intracellular pH homeostasis to delay coronavirus infectious bronchitis virus cell entry via sodium hydrogen exchanger 3 activation

文献类型： 外文期刊

第一作者： Dai, Jun

作者： Dai, Jun;Feng, Yiyi;Liao, Ying;Tan, Lei;Sun, Yingjie;Song, Cuiping;Qiu, Xusheng;Ding, Chan;Dai, Jun;Long, Hong;Ding, Chan

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关键词： dexamethasone; coronavirus; infectious bronchitis virus; Na+/H(+)exchanger 3; pH

期刊名称：JOURNAL OF VIROLOGY （ 影响因子：3.8； 五年影响因子：3.9 ）

ISSN： 0022-538X

年卷期： 2025 年 99 卷 6 期

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收录情况： SCI

摘要： Coronavirus entry into host cells enables the virus to initiate its replication cycle efficiently while evading host immune response. Cell entry is intricately associated with pH levels in the cytoplasm or endosomes. In this study, we observed that the sodium hydrogen exchanger 3 (Na+/H+ exchanger 3 or NHE3), which is strongly activated by dexamethasone (Dex) to promote cell membrane Na+/H+ exchange, was critical for cytoplasmic and endosomal acidification. Dex activates NHE3, which increases intracellular pH and blocks the initiation of coronavirus infectious bronchitis virus (IBV) negative-stranded genomic RNA synthesis. Also, Dex antiviral effects are relieved by the glucocorticoid receptor (GR) antagonist RU486 and the NHE3 selective inhibitor tenapanor. These results show that Dex antiviral effects depend on GR and NHE3 activities. Furthermore, Dex exhibits remarkable dose-dependent inhibition of IBV replication, although its antiviral effects are constrained by specific virus and cell types. To our knowledge, this is the first report to show that Dex helps suppress the entry of coronavirus IBV into cells by promoting proton leak pathways, as well as by precisely tuning luminal pH levels mediated by NHE3. Disrupted cytoplasmic pH homeostasis, triggered by Dex and NHE3, plays a crucial role in impeding coronavirus IBV replication. Therefore, cytoplasmic pH plays an essential role during IBV cell entry, probably assisting viruses at the fusion and/or uncoating stages. The strategic modulation of NHE3 activity to regulate intracellular pH could provide a compelling mechanism when developing potent anti-coronavirus drugs.

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