Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Cell Mol Immunol. 2010 Jul;7(4):263-70. doi: 10.1038/cmi.2010.25. Epub 2010 May 17.
Historically, influenza pandemics have arisen from avian influenza viruses. Avian influenza viruses H5N1 and H9N2 are potential pandemic candidates. Infection of humans with the highly pathogenic avian influenza H5N1 virus is associated with a mortality in excess of 60%, which has been attributed to dysregulation of the cytokine system. Human macrophages and epithelial cells infected with some genotypes of H5N1 and H9N2 viruses express markedly elevated cytokine and chemokine levels when compared with seasonal influenza A subtype H1N1 virus. The mechanisms underlying this cytokine and chemokine hyperinduction are not fully elucidated. In the present study, we demonstrate that autophagy, a tightly regulated homeostatic process for self-digestion of unwanted cellular subcomponents, plays a role in cytokine induction. Autophagy is induced to a greater extent by H9N2/G1, in association with cytokine hyperinduction, compared with H1N1 and the novel pandemic swine-origin influenza A/H1N1 viruses. Using 3-methyladenine to inhibit autophagy and small interfering RNA to silence the autophagy gene, Atg5, we further show that autophagic responses play a role in influenza virus-induced CXCL10 and interferon-alpha expression in primary human blood macrophages. Our results provide new insights into the pathogenic mechanisms of avian influenza viruses.
从历史上看，流感大流行是由禽流感病毒引起的。禽流感病毒 H5N1 和 H9N2 是潜在的大流行候选病毒。高致病性禽流感 H5N1 病毒感染人类的死亡率超过 60%，这归因于细胞因子系统的失调。与季节性甲型流感 H1N1 病毒相比，人类巨噬细胞和上皮细胞感染某些基因型的 H5N1 和 H9N2 病毒时，细胞因子和趋化因子的表达水平显著升高。这种细胞因子和趋化因子过度诱导的机制尚未完全阐明。在本研究中，我们证明了自噬，一种用于自我消化不需要的细胞亚成分的严格调节的体内平衡过程，在细胞因子诱导中发挥作用。与 H1N1 和新型大流行猪源甲型流感 A/H1N1 病毒相比，H9N2/G1 病毒更能诱导自噬，同时也导致细胞因子的过度诱导。我们使用 3-甲基腺嘌呤抑制自噬，并使用小干扰 RNA 沉默自噬基因 Atg5，进一步表明自噬反应在流感病毒诱导原代人血巨噬细胞中 CXCL10 和干扰素-α的表达中发挥作用。我们的研究结果为禽流感病毒的致病机制提供了新的见解。
