Induction of type I interferon by adenovirus-encoded small RNAs
Induction of type I interferon by adenovirus-encoded small RNAs
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DOI：
10.1073/pnas.1009823107
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发表时间：
2010-10-05
影响因子：
11.1
通讯作者：
Mizuguchi, Hiroyuki
中科院分区：
文献类型：
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作者：
Yamaguchi, Tomoko;Kawabata, Kenji;Mizuguchi, Hiroyuki
用复制缺陷型重组腺病毒（Ad）载体转导导致先天免疫应答的快速激活，例如炎性细胞因子产生和随后的组织损伤。Ad载体诱导的先天免疫应答的确切机制仍有待阐明。激活先天免疫应答的Ad载体的可能组分是衣壳蛋白、病毒基因组（DNA）和病毒转录物。在本研究中，我们证明了病毒相关RNA（VA-RNA），这是由RNA聚合酶III转录的小RNA，诱导产生I型IFN（IFN-α和IFN-β），但它们不诱导炎性细胞因子的产生（IL-6和IL-12），在小鼠胚胎成纤维细胞（MEF）和粒细胞-巨噬细胞集落刺激因子产生的骨髓来源的树突状细胞（GM-DC）。我们还表明，IFN-β启动子刺激因子-1是参与VA-RNA依赖的IFN-β的生产在MEFs和部分参与在GM-DCs的I型IFN的生产。本研究为深入了解Ad载体引发的先天性免疫应答机制提供了重要的线索，为基因治疗和疫苗应用提供了更先进、更合理的Ad载体设计。
Transduction with replication-incompetent recombinant adenovirus (Ad) vectors results in a rapid activation of innate immune responses, such as inflammatory cytokine production and subsequent tissue damage. The precise mechanisms of the innate immune responses induced by Ad vectors remain to be clarified. Possible components of Ad vectors that activate innate immune responses are the capsid protein, the viral genome (DNA), and viral transcripts. In the present study, we demonstrate that virus-associated RNAs (VA-RNAs), which are small RNAs transcribed by RNA polymerase III, induce the production of type I IFN (IFN-alpha and IFN-beta), but they do not induce the production of inflammatory cytokines (IL-6 and IL-12), in mouse embryonic fibroblasts (MEFs) and granulocyte-macrophage colony-stimulating factor-generated bone marrow-derived dendritic cells (GM-DCs). We also show that IFN-beta promoter stimulator-1 is involved in VA-RNA-dependent IFN-beta production in MEFs and is partially involved in type I IFN production in GM-DCs. This study provides important insight into the mechanisms of Ad vector-triggered innate immune responses, which may lead to more advanced and rational Ad vector designs for gene therapies and vaccine applications.