Human Respiratory Syncytial Virus Nucleoprotein and Inclusion Bodies Antagonize the Innate Immune Response Mediated by MDA5 and MAVS
Human Respiratory Syncytial Virus Nucleoprotein and Inclusion Bodies Antagonize the Innate Immune Response Mediated by MDA5 and MAVS
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DOI：
10.1128/jvi.00215-12
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发表时间：
2012-08-01
影响因子：
5.4
通讯作者：
Santangelo, Philip J.
中科院分区：
文献类型：
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作者：
Lifland, Aaron W.;Jung, Jeenah;Santangelo, Philip J.
目前，人呼吸道合胞病毒（hRSV）蛋白和RNA在感染细胞中的空间分布仍在研究中，关于病毒诱导的结构和先天免疫系统的相互作用有许多未回答的问题。很少有研究hRSV使用亚细胞成像作为一种手段来探索响应于感染和病毒结构形成的维甲酸诱导基因-I（RIG-I）样受体或线粒体抗病毒信号传导（MAVS）蛋白的定位变化。在这项研究中，我们发现RIG-I和黑色素瘤分化相关基因5（MDA 5）与病毒基因组RNA和核蛋白（N）共定位早在感染后6小时（hpi）。到12 hpi时，在大的病毒包涵体（IB）内观察到MDA 5和MAVS。我们使用邻近连接试验（PLA），并确定在整个感染过程中，N蛋白与IBs中的MDA 5和MAVS非常接近。在N和磷蛋白（P）的瞬时共表达中也发现了类似的结果。此外，我们证明了在纽卡斯尔病病毒感染后，IBs中MDA 5和MAVS的定位抑制干扰素β mRNA的表达27倍。从这些数据中，我们得出结论，N可能与MDA 5相互作用，与MAVS非常接近，并将这些分子定位在IB内以减弱干扰素应答。据我们所知，这是首次报道hRSV IB的特异性功能和hRSV N蛋白作为先天免疫应答的调节剂。
Currently, the spatial distribution of human respiratory syncytial virus (hRSV) proteins and RNAs in infected cells is still under investigation, with many unanswered questions regarding the interaction of virus-induced structures and the innate immune system. Very few studies of hRSV have used subcellular imaging as a means to explore the changes in localization of retinoicacid-inducible gene-I (RIG-I)-like receptors or the mitochondrial antiviral signaling (MAVS) protein, in response to the infection and formation of viral structures. In this investigation, we found that both RIG-I and melanoma differentiation-associated gene 5 (MDA5) colocalized with viral genomic RNA and the nucleoprotein (N) as early as 6 h postinfection (hpi). By 12 hpi, MDA5 and MAVS were observed within large viral inclusion bodies (IB). We used a proximity ligation assay (PLA) and determined that the N protein was in close proximity to MDA5 and MAVS in IBs throughout the course of the infection. Similar results were found with the transient coexpression of N and the phosphoprotein (P). Additionally, we demonstrated that the localization of MDA5 and MAVS in IBs inhibited the expression of interferon beta mRNA 27-fold following Newcastle disease virus infection. From these data, we concluded that the N likely interacts with MDA5, is in close proximity to MAVS, and localizes these molecules within IBs in order to attenuate the interferon response. To our knowledge, this is the first report of a specific function for hRSV IBs and of the hRSV N protein as a modulator of the innate immune response.