Influenza H5N1 and H1N1 virus replication and innate immune responses in bronchial epithelial cells are influenced by the state of differentiation.
Influenza H5N1 and H1N1 virus replication and innate immune responses in bronchial epithelial cells are influenced by the state of differentiation.
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支气管上皮细胞中的流感H5N1和H1N1病毒复制和先天免疫反应受分化状态的影响。
DOI：
10.1371/journal.pone.0008713
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发表时间：
2010-01-15
期刊：
影响因子：
3.7
通讯作者：
Chan MC
中科院分区：
文献类型：
--
作者：
Chan RW;Yuen KM;Yu WC;Ho CC;Nicholls JM;Peiris JS;Chan MC
H5 N1流感病毒继续在家禽中流行，并通过动物源性途径传播给人类。虽然猪源H1N1病毒已成为大流行，但与人畜共患H5 N1疾病相比，其对人类的毒力仍然很低。由于人呼吸道上皮是流感病毒的主要靶细胞，阐明H5 N1流感病毒在人支气管上皮中的病毒嗜性和宿主天然免疫应答可能有助于了解其发病机制。本研究建立了未分化和分化良好的正常人支气管上皮（NHBE）细胞的原代培养体系，并分别用高致病性H5 N1流感病毒（A/Vietnam/3046/2004）和季节性H1N1流感病毒（A/Hong Kong/54/1998）感染NHBE细胞，采用qPCR和ELISA方法比较病毒复制动力学和细胞因子及趋化因子反应。我们发现，在体外培养的分化良好的NHBE细胞获得了正常人支气管组织的生理特性，表达高水平的α2-6-连接唾液酸受体和人气道胰蛋白酶样（HAT）蛋白酶，而在未分化的NHBE细胞中的低表达。与H1N1病毒相比，H5 N1病毒复制更有效，并在未分化的NHBE细胞中诱导更强的I型干扰素应答。相比之下，在分化良好的培养物中，H5 N1病毒复制效率较低，并且与H1N1病毒相比引起较低的干扰素-β反应。我们的数据表明，支气管上皮细胞的分化对细胞对人H1N1和禽H5 N1病毒的容许性以及宿主的先天免疫应答具有重要影响。降低的病毒复制效率部分地解释了流感H5 N1病毒感染的分化良好的NHBE细胞中较低的干扰素-β应答。由于支气管上皮中的流感感染将导致组织损伤并与上皮再生相关，因此从未分化的NHBE培养物产生的数据也可能与疾病发病机制相关。
Influenza H5N1 virus continues to be enzootic in poultry and transmits zoonotically to humans. Although a swine-origin H1N1 virus has emerged to become pandemic, its virulence for humans remains modest in comparison to that seen in zoonotic H5N1 disease. As human respiratory epithelium is the primary target cells for influenza viruses, elucidating the viral tropism and host innate immune responses of influenza H5N1 virus in human bronchial epithelium may help to understand the pathogenesis. Here we established primary culture of undifferentiated and well differentiated normal human bronchial epithelial (NHBE) cells and infected with highly pathogenic influenza H5N1 virus (A/Vietnam/3046/2004) and a seasonal influenza H1N1 virus (A/Hong Kong/54/1998), the viral replication kinetics and cytokine and chemokine responses were compared by qPCR and ELISA. We found that the in vitro culture of the well differentiated NHBE cells acquired the physiological properties of normal human bronchi tissue which express high level of α2-6-linked sialic acid receptors and human airway trypsin-like (HAT) protease, in contrast to the low expression in the non-differentiated NHBE cells. When compared to H1N1 virus, the H5N1 virus replicated more efficiently and induced a stronger type I interferon response in the undifferentiated NHBE cells. In contrast, in well differentiated cultures, H5N1 virus replication was less efficient and elicited a lower interferon-beta response in comparison with H1N1 virus. Our data suggest that the differentiation of bronchial epithelial cells has a major influence in cells' permissiveness to human H1N1 and avian H5N1 viruses and the host innate immune responses. The reduced virus replication efficiency partially accounts for the lower interferon-beta responses in influenza H5N1 virus infected well differentiated NHBE cells. Since influenza infection in the bronchial epithelium will lead to tissue damage and associate with the epithelium regeneration, the data generated from the undifferentiated NHBE cultures may also be relevant to disease pathogenesis.
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