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

麻疹是一种具有高度传染性的病毒性疾病，伴有发热和皮疹，尤其在儿科。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，可能是由于免疫抑制在继发性感染中的作用。在本研究中，我们提出了一种新的MeV在单核细胞中的免疫抑制机制。我们发现病毒诱导的和脂多糖（LPS）诱导的NF-κB和AP-1的激活在感染MeV的单核细胞中被抑制，但在感染的上皮细胞中不被抑制。在感染细胞中，LPS处理未能诱导形成含有TAK1、TAB2和TRAF6的活性蛋白激酶复合物，该复合物与含有IRAK1的toll样受体复合物分离。泛素修饰酶A20是一种NF-κB依赖性基因，是宿主对NF-κB的负反馈调节因子，在感染的单核细胞中显著上调，而在感染的上皮细胞中没有上调。我们证明了MeV磷酸化蛋白（P蛋白）的表达对于a20的诱导是必要和充分的。A20启动子中的负调控基序（ELIE基序）对MeV对A20的转录上调起重要作用。P蛋白间接与ELIE基序相互作用，释放对A20转录的抑制，不依赖于NF-κB。在MeV感染的单核细胞中，抑制NF-κB和AP-1的激活，即免疫沉默，可能是MeV利用的一种策略，以避免排斥反应，并允许感染通过血流扩散到整个身体。我们认为p缺陷MeV是一种候选的活疫苗，它不会引起免疫抑制。

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.