Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, China.
J Infect Dis. 2011 Dec 15;204(12):1866-78. doi: 10.1093/infdis/jir665. Epub 2011 Oct 19.
Highly pathogenic avian influenza H5N1 viruses cause severe disease in humans, and dysregulation of cytokine responses is believed to contribute to the pathogenesis of human H5N1 disease. However, mechanisms leading to the increased induction of proinflammatory cytokines by H5N1 viruses are poorly understood. We show that the innate sensing receptor RIG-I is involved in interferon regulatory factor 3 (IRF3), NF-κB nuclear translocation, p38 activation, and the subsequent interferon (IFN) β, IFN-λ1, and tumor necrosis factor α induction during H5N1 infection. Soluble mediators from H5N1-infected human macrophages upregulate RIG-I, MDA5, and TLR3 to much higher levels than those from seasonal H1N1 in uninfected human macrophages and alveolar epithelial cells via paracrine IFNAR1/JAK but not IFN-λ receptor signaling. Compared with H1N1 virus-induced mediators, H5N1 mediators markedly enhance the cytokine response to PolyIC and to both seasonal and H5N1 virus infection in a RIG-I-dependent manner. Thus, sensitizing neighboring cells by upregulation of RIG-I contributes to the amplified cytokine cascades during H5N1 infection.
高致病性禽流感 H5N1 病毒可导致人类罹患重病，细胞因子反应失调被认为是导致人类 H5N1 疾病发病机制的原因之一。然而，导致 H5N1 病毒引起促炎细胞因子过度诱导的机制尚不清楚。我们发现，天然感应受体 RIG-I 参与了干扰素调节因子 3（IRF3）、NF-κB 核易位、p38 激活，以及随后 H5N1 感染期间干扰素（IFN）β、IFN-λ1 和肿瘤坏死因子 α 的诱导。H5N1 感染的人巨噬细胞中的可溶性介质通过旁分泌 IFNAR1/JAK 而不是 IFN-λ 受体信号，将 RIG-I、MDA5 和 TLR3 的上调水平比未感染的人巨噬细胞和肺泡上皮细胞中季节性 H1N1 的上调水平高得多。与 H1N1 病毒诱导的介质相比，H5N1 介质通过 RIG-I 依赖性方式显著增强了对 PolyIC 以及季节性和 H5N1 病毒感染的细胞因子反应。因此，通过上调 RIG-I 使邻近细胞致敏有助于在 H5N1 感染期间放大细胞因子级联反应。
