Highly pathogenic avian influenza H5N1 virus delays apoptotic responses via activation of STAT3.
Highly pathogenic avian influenza H5N1 virus delays apoptotic responses via activation of STAT3.
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DOI：
10.1038/srep28593
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发表时间：
2016-06-27
影响因子：
4.6
通讯作者：
Chan MC
中科院分区：
文献类型：
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作者：
Hui KP;Li HS;Cheung MC;Chan RW;Yuen KM;Mok CK;Nicholls JM;Peiris JS;Chan MC
高致病性禽流感 (HPAI) H5N1 病毒继续构成大流行威胁，但人们对其发病机制缺乏了解。我们使用生理相关的呼吸道上皮细胞比较了 HPAI H5N1 和低致病性 H1N1 病毒引发的细胞凋亡反应。我们证明，与 H1N1 病毒相比，H5N1 病毒延迟了原代人支气管和肺泡上皮细胞 (AEC) 的凋亡。 AEC 中的 caspase-8 和 -9 均被 H5N1 和 H1N1 病毒激活，而 H5N1 则差异上调 TRAIL。 TRAIL 受体沉默可减少 H5N1 诱导的细胞凋亡。更重要的是，STAT3敲除增加了H5N1感染引起的细胞凋亡，表明H5N1病毒通过激活STAT3来延迟细胞凋亡。综上所述，我们证明与 H1N1 相比，STAT3 参与了 H5N1 延迟的细胞凋亡。由于细胞凋亡的延迟延长了病毒复制和 H5N1 感染细胞产生促炎细胞因子和 TRAIL 的持续时间，这有助于协调细胞因子风暴和组织损伤，因此我们的结果表明 STAT3 可能在 H5N1 发病机制中发挥着以前未曾怀疑的作用。
Highly pathogenic avian influenza (HPAI) H5N1 virus continues to pose pandemic threat, but there is a lack of understanding of its pathogenesis. We compared the apoptotic responses triggered by HPAI H5N1 and low pathogenic H1N1 viruses using physiologically relevant respiratory epithelial cells. We demonstrated that H5N1 viruses delayed apoptosis in primary human bronchial and alveolar epithelial cells (AECs) compared to H1N1 virus. Both caspase-8 and -9 were activated by H5N1 and H1N1 viruses in AECs, while H5N1 differentially up-regulated TRAIL. H5N1-induced apoptosis was reduced by TRAIL receptor silencing. More importantly, STAT3 knock-down increased apoptosis by H5N1 infection suggesting that H5N1 virus delays apoptosis through activation of STAT3. Taken together, we demonstrate that STAT3 is involved in H5N1-delayed apoptosis compared to H1N1. Since delay in apoptosis prolongs the duration of virus replication and production of pro-inflammatory cytokines and TRAIL from H5N1-infected cells, which contribute to orchestrate cytokine storm and tissue damage, our results suggest that STAT3 may play a previously unsuspected role in H5N1 pathogenesis.