Host Immune and Apoptotic Responses to Avian Influenza Virus H9N2 in Human Tracheobronchial Epithelial Cells
Host Immune and Apoptotic Responses to Avian Influenza Virus H9N2 in Human Tracheobronchial Epithelial Cells
复制标题
人气管支气管上皮细胞对禽流感病毒 H9N2 的宿主免疫和细胞凋亡反应。
DOI：
10.1165/rcmb.2009-0120oc
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发表时间：
2011-01-01
影响因子：
6.4
通讯作者：
Cardona, Carol J.
中科院分区：
文献类型：
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作者：
Xing, Zheng;Harper, Richart;Cardona, Carol J.
H9 N2亚型禽流感病毒在野鸟中传播，在家禽中流行，并已成功跨越物种界限感染人类。系统发育分析显示，该亚型病毒似乎有助于产生高致病性H5 N1病毒。关于宿主对H9 N2病毒在人呼吸道上皮细胞中的反应知之甚少，呼吸道上皮细胞是病毒感染的主要门户。使用顶端分化的原代人气管支气管上皮细胞（TBE）培养，我们研究了宿主对禽H9 N2病毒感染的免疫反应，并与人H9 N2分离株进行了比较。我们发现IFN-β是主要的抗病毒成分，而干扰素γ诱导蛋白10 kDa（IP-10）、趋化因子（C-C基序）配体（CCL）-5和TNF-α可能在H9 N2病毒的促炎反应中起关键作用。相比之下，促炎性IL-1β、IL-8甚至IL-6在致病性中可能仅起次要作用。Toll样受体（TLR）-3、TLR-7和黑色素瘤分化相关基因5（MDA-5）参与了机体对H9 N2病毒的天然免疫，MDA-5在IFN-β的诱导中起重要作用。我们发现，禽H9 N2病毒诱导细胞凋亡，通过线粒体/细胞色素c介导的内在途径，除了caspase 8介导的外在途径，证明了活性caspase 9和细胞色素c的胞质存在，独立于截短的BH 3相互作用域死亡激动剂（Bid）激活。此外，我们证明FLICE样抑制蛋白（FLIP），一种凋亡的双重调节因子，和p53依赖的Bcl-2家族成员Bax和Bcl-x（s），似乎分别参与了外源性和内源性凋亡途径的调节。本研究的结果将进一步加深我们对H9 N2流感病毒在人类呼吸道上皮细胞中的宿主防御机制和致病机制的理解。
The avian influenza virus H9N2 subtype has circulated in wild birds, is prevalent in domestic poultry, and has successfully crossed the species boundary to infect humans. Phylogenetic analyses showed that viruses of this subtype appear to have contributed to the generation of highly pathogenic H5N1 viruses. Little is known about the host responses to H9N2 viruses in human airway respiratory epithelium, the primary portal for viral infection. Using an apically differentiated primary human tracheobronchial epithelial (TBE) culture, we examined host immune responses to infection by an avian H9N2 virus, in comparison with a human H9N2 isolate. We found that IFN-β was the prominent antiviral component, whereas interferon gamma-induced protein 10 kDa (IP-10), chemokine (C-C motif) ligand (CCL)-5 and TNF-α may be critical in proinflammatory responses to H9N2 viruses. In contrast, proinflammatory IL-1β, IL-8, and even IL-6 may only play a minor role in pathogenicity. Apparently Toll-like receptor (TLR)-3, TLR-7, and melanoma differentiation-associated gene 5 (MDA-5) contributed to the innate immunity against the H9N2 viruses, and MDA-5 was important in the induction of IFN-β. We showed that the avian H9N2 virus induced apoptosis through the mitochondria/cytochrome c-mediated intrinsic pathway, in addition to the caspase 8-mediated extrinsic pathway, as evidenced by the cytosolic presence of active caspase 9 and cytochrome c, independent of truncated BH3 interacting domain death agonist (Bid) activation. Further, we demonstrated that FLICE-like inhibitory protein (FLIP), an apoptotic dual regulator, and the p53-dependent Bcl-2 family members, Bax and Bcl-x(s), appeared to be involved in the regulation of extrinsic and intrinsic apoptotic pathways, respectively. The findings in this study will further our understanding of host defense mechanisms and the pathogenesis of H9N2 influenza viruses in human respiratory epithelium.