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首页> 美国卫生研究院文献>Journal of Virology >Highly Pathogenic Avian Influenza H5N1 Viruses Elicit an Attenuated Type I Interferon Response in Polarized Human Bronchial Epithelial Cells
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Highly Pathogenic Avian Influenza H5N1 Viruses Elicit an Attenuated Type I Interferon Response in Polarized Human Bronchial Epithelial Cells

机译：高度致病性禽流感H5N1病毒在极化的人支气管上皮细胞中引起减弱的I型干扰素反应。

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The unparalleled spread of highly pathogenic avian influenza A (HPAI) H5N1 viruses has resulted in devastating outbreaks in domestic poultry and sporadic human infections with a high fatality rate. To better understand the mechanism(s) of H5N1 virus pathogenesis and host responses in humans, we utilized a polarized human bronchial epithelial cell model that expresses both avian alpha-2,3- and human alpha-2,6-linked sialic acid receptors on the apical surface and supports productive replication of both H5N1 and H3N2 viruses. Using this model, we compared the abilities of selected 2004 HPAI H5N1 viruses isolated from humans and a recent human H3N2 virus to trigger the type I interferon (IFN) response. H5N1 viruses elicited significantly less IFN regulatory factor 3 (IRF3) nuclear translocation, as well as delayed and reduced production of IFN-β compared with the H3N2 virus. Furthermore, phosphorylation of Stat2 and induction of IFN-stimulated genes (ISGs), such as MX1, ISG15, IRF7, and retinoic acid-inducible gene I, were substantially delayed and reduced in cells infected with H5N1 viruses. We also observed that the highly virulent H5N1 virus replicated more efficiently and induced a weaker IFN response than the H5N1 virus that exhibited low virulence in mammals in an earlier study. Our data suggest that the H5N1 viruses tested, especially the virus with the high-pathogenicity phenotype, possess greater capability to attenuate the type I IFN response than the human H3N2 virus. The attenuation of this critical host innate immune defense may contribute to the virulence of H5N1 viruses observed in humans.
机译：高致病性甲型禽流感（HPAI）H5N1病毒的无与伦比的传播已导致家禽的毁灭性爆发和高致死率的零星人类感染。为了更好地了解人类中H5N1病毒的发病机理和宿主反应的机制，我们使用了极化的人支气管上皮细胞模型，该模型在细胞上表达禽类α-2,3-和人α-2,6-连接的唾液酸受体。顶表面并支持H5N1和H3N2病毒的高效复制。使用此模型，我们比较了从人类中分离出的2004年HPAI H5N1病毒与最近的人类H3N2病毒触发I型干扰素（IFN）应答的能力。与H3N2病毒相比，H5N1病毒引起的IFN调节因子3（IRF3）核易位明显减少，并且IFN-β的产生延迟和减少。此外，在感染了H5N1病毒的细胞中，Stat2的磷酸化和IFN刺激的基因（ISG）（例如MX1，ISG15，IRF7和视黄酸诱导的基因I）的诱导被大大延迟和减少。我们还观察到，与H5N1病毒在哺乳动物中表现出低毒力相比，高毒力H5N1病毒能够更有效地复制并诱导更弱的IFN反应。我们的数据表明，所测试的H5N1病毒，特别是具有高致病性表型的病毒，具有比人H3N2病毒更大的减弱I型IFN反应的能力。该关键宿主固有免疫防御能力的减弱可能有助于在人类中观察到H5N1病毒的毒性。

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