Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA
Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA
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DOI：
10.1038/nature07106
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发表时间：
2008-07-24
期刊：
影响因子：
64.8
通讯作者：
Gale, Michael, Jr.
中科院分区：
文献类型：
--
作者：
Saito, Takeshi;Owen, David M.;Gale, Michael, Jr.
先天性免疫防御对于控制病毒感染至关重要，它是通过宿主对被称为病原体相关分子模式（PAMPs）的病毒大分子基序的识别而触发的（1）。丙型肝炎病毒（HCV）是一种在肝脏中复制的RNA病毒，全球有2亿人感染（2）。感染受到由细胞RIG - I解旋酶触发的肝脏免疫防御的调控。RIG - I结合PAMP RNA并发出信号激活干扰素调节因子3，以诱导干扰素 - α/β以及限制感染的抗病毒/干扰素刺激基因（ISGs）的表达（3 - 10）。在此，我们确定了HCV基因组3'非翻译区的多聚尿苷酸基序及其复制中间体是RIG - I的PAMP底物，并表明RNA病毒基因组中存在的这种以及类似的同聚尿苷酸或同聚核糖腺苷酸基序是人类和鼠类细胞中RIG - I识别和免疫触发的主要特征（8）。PAMP RNA上的5'末端三磷酸是RIG - I结合所必需的，但并不充分，RIG - I结合主要取决于同聚核糖核苷酸组成、线性结构和长度。HCV PAMP RNA刺激RIG - I依赖性信号传导，在体内诱导肝脏先天性免疫反应，并在体外触发干扰素和ISG表达以抑制HCV感染。这些结果通过将HCV和其他RNA病毒基因组内的特定同聚RNA基序定义为RIG - I的PAMP底物，在概念上取得了进展，并证明了PAMP - RIG - I相互作用的免疫原性特征，这些特征可作为疫苗和免疫治疗方法的免疫佐剂。
Innate immune defences are essential for the control of virus infection and are triggered through host recognition of viral macromolecular motifs known as pathogen-associated molecular patterns (PAMPs)(1). Hepatitis C virus (HCV) is an RNA virus that replicates in the liver, and infects 200 million people worldwide(2). Infection is regulated by hepatic immune defences triggered by the cellular RIG-I helicase. RIG-I binds PAMP RNA and signals interferon regulatory factor 3 activation to induce the expression of interferon-alpha/beta and antiviral/interferon-stimulated genes (ISGs) that limit infection(3-10). Here we identify the polyuridine motif of the HCV genome 3 ' non-translated region and its replication intermediate as the PAMP substrate of RIG-I, and show that this and similar homopolyuridine or homopolyriboadenine motifs present in the genomes of RNA viruses are the chief feature of RIG-I recognition and immune triggering in human and murine cells(8). 5 ' terminal triphosphate on the PAMP RNA was necessary but not sufficient for RIG-I binding, which was primarily dependent on homopolymeric ribonucleotide composition, linear structure and length. The HCV PAMP RNA stimulated RIG-I-dependent signalling to induce a hepatic innate immune response in vivo, and triggered interferon and ISG expression to suppress HCV infection in vitro. These results provide a conceptual advance by defining specific homopolymeric RNA motifs within the genome of HCV and other RNA viruses as the PAMP substrate of RIG-I, and demonstrate immunogenic features of the PAMP-RIG-I interaction that could be used as an immune adjuvant for vaccine and immunotherapy approaches.