H5N1 Influenza Virus-Induced Mediators Upregulate RIG-I in Uninfected Cells by Paracrine Effects Contributing to Amplified Cytokine Cascades
H5N1 Influenza Virus-Induced Mediators Upregulate RIG-I in Uninfected Cells by Paracrine Effects Contributing to Amplified Cytokine Cascades
复制标题
DOI：
10.1093/infdis/jir665
复制
发表时间：
2011-12-15
影响因子：
6.4
通讯作者：
Peiris, J. S. M.
中科院分区：
文献类型：
--
作者：
Hui, Kenrie P. Y.;Lee, Suki M. Y.;Peiris, J. S. M.
高致病性禽流感H5 N1病毒在人类中引起严重的疾病，并且细胞因子反应的失调被认为有助于人类H5 N1疾病的发病机制。然而，导致H5 N1病毒诱导促炎细胞因子增加的机制知之甚少。我们表明，先天感应受体RIG-I参与干扰素调节因子3（IRF 3），NF-κ B核转位，p38激活，以及随后的干扰素（IFN）β，IFN-λ 1，和肿瘤坏死因子α诱导在H5 N1感染。在未感染的人巨噬细胞和肺泡上皮细胞中，来自H5 N1感染的人巨噬细胞的可溶性介质通过旁分泌IFNAR 1/JAK而不是IFN-lambda受体信号传导将RIG-I、MDA 5和TLR 3上调至比来自季节性H1N1的那些更高的水平。与H1N1病毒诱导的介质相比，H5 N1介质以RIG-I依赖的方式显著增强对PolyIC以及对季节性和H5 N1病毒感染的细胞因子应答。因此，通过上调RIG-I使邻近细胞敏感有助于H5 N1感染期间放大的细胞因子级联。
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-kappa B nuclear translocation, p38 activation, and the subsequent interferon (IFN) beta, IFN-lambda 1, and tumor necrosis factor alpha 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-lambda 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.