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Basic scientific research for formulating antiviral agents focusing on the immunosuppressive mechanism of virus

聚焦病毒免疫抑制机制的抗病毒药物基础科学研究

基本信息

批准号：
18590062
负责人：
YOKOTA Shin-ichi
金额：
$ 2.57万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

Measles is a highly contagious viral diseases with fever and rash, particularly in pediatric. Suppression of the host immune response by measles virus (MeV) is a major cause of the high morbidity and mortality rates of acute measles, perhaps due to the role of immunosuppression in secondary infection. In the present study, we propose a novel immunosuppression mechanism of MeV in monocytic cells.We found that the virus-induced and lipopolysaccharide (LPS)-induced activation of NF-κB and AP-1 was suppressed in monocytic cells infected with MeV, but not in infected epithelial cells. In the infected cells, LPS treatment failed to induce formation of active protein kinase complex containing TAK1, TAB2 and TRAF6, which dissociates from Toll-like receptor complexes containing IRAK1.Ubiquitin-modifying enzyme A20, which is an NF-κB-dependent gene and a host negative feedback regulator of NF-κB, was dramatically upregulated in infected monocytic cells, but not in infected epithelial cells. We demonstrated that MeV phosphoprotein (P protein) expression was necessary and sufficient for the induction ofA20. A negative regulatory motif (ELIE motif) in the A20 promoter was important for transcriptional upregulation of A20 by MeV. And the P protein interacted indirectly with the ELIE motif, and released the suppression of A20 transcription, independent to NF-κB.Suppression of NF-κB and AP-1 activation, namely immunological silencing, in MeV-infected monocytic cells may be a strategy utilized by MeV to escape rejection and allow the spread of infection throughout the entire body via the blood stream. We consider that P-deficient MeV is a candidate for live-vaccine, which does not cause immunosuppression.

麻疹是一种以发热和皮疹为特征的高度传染性病毒性疾病，尤其是在儿科。麻疹病毒（MeV）对宿主免疫反应的抑制是急性麻疹高发病率和死亡率的主要原因，这可能是由于免疫抑制在继发感染中的作用。在本研究中，我们提出了一种新的免疫抑制机制，我们发现，病毒和脂多糖（LPS）诱导的NF-κB和AP-1的激活抑制在单核细胞感染MeV，但在感染的上皮细胞。在感染的细胞中，LPS处理未能诱导含有TEK 1、TAB 2和TRAF 6的活性蛋白激酶复合物的形成，该复合物与含有IRAK 1的Toll样受体复合物解离。泛肽修饰酶A20是一种NF-κ B依赖性基因，也是NF-κB的宿主负反馈调节因子。在感染的单核细胞中，表达显着上调，但在感染的上皮细胞中则没有。B。我们证明了MeV磷蛋白（P蛋白）的表达是诱导A20的必要和充分的。A20启动子中的负调控基序（ELIE基序）对于MeV上调A20的转录是重要的。P蛋白与ELIE基序间接相互作用，解除了对A20转录的抑制，而不依赖于NF-κB。抑制NF-κB和AP-1的激活，即免疫沉默，可能是MeV逃避排斥反应，通过血流将感染扩散到全身的一种策略。我们认为P缺陷MeV是活疫苗的候选者，它不会引起免疫抑制。