Mechanism of immune suppression induced by measles virus

麻疹病毒引起的免疫抑制机制

基本信息

批准号：
10470083
负责人：
SEYA Tsukasa
金额：
$ 3.2万
依托单位：
OSAKA MEDICAL CENTER FOR CANCER AND CARDIOVASCULAR DISEASES
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B).
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10470083/
关键词：
measles virus human CD46 signal transduction SHP-1 CD9 α3 β1 integrin moesin immune suppression α_3β_1インテグリン麻疹ウィルス innate immunity(基本免疫)抗原提示細胞 IL-12 ホスファターゼ補体

项目摘要

Human CD46, formerly membrane co factor protein (MCP), binds and inactivates complement C3b and serves as a receptor for measles virus (MV), thereby protecting cells from homologous complement and sustaining systemic measles infection. Suppression of cell-mediated immunity including down-regulation of IL-12 production has been reported on macrophages (Mφ) by crosslinking their CD46. The intracellular events responsible for these immune responses, however, remain unknown. Here, we found that 6-8 day GM-CSF-treated peripheral blood monocytes acquired the capacity to recruit SHP-1 to their CD46 and concomitantly were able to produce IL-12 p40 and nitric oxide (NO). Within the same time frame, Mφ acquired the capacity to assemble CD9, alphaS betal integrin to their CD46. Mφ earlier to this maturation stage were able to potentiate MV (Edmonston and Nagahata strain) replication, but in the activation stage NO and cytokines were induced and MV replication was severely suppressed. Direct ligation of CD46 by C3b, mAbs F(ab')_2 or MV H/F glycoproteins, but not intracellular MV replication, was required for these cellular responses. Interestingly, the KO strain failed to replicate in the 6-8 day GM-CSF-cultured Mφ while other MV strains replicated to form syncytia under the same conditions. When stimulated with the KO strain, rapid and transient dissociation of SHP-1 from CD46 was observed. Taken together, CD46 first serves as a receptor for MV, then recruits a molecular complex as depending upon maturation stages of human Mφ. These results provide strong evidence that CD46 serves as a signal-transducing molecule and that the properties of ligands determine suppression or activation of innate immune system. MV-mediated immune suppression may in part be attributable to the CD46 signaling.

人CD46（以前是膜的co蛋白（MCP））结合并失活的补体C3B并用作麻疹病毒（MV）的受体，从而保护细胞免受同源的完成和持续的全身麻疹感染。通过交联通过交联CD46，已经报道了细胞介导的免疫抑制的抑制，包括巨噬细胞（Mφ）的下调IL-12的下调。然而，负责这些免疫复杂的细胞内事件仍然未知。在这里，我们发现经GM-CSF处理的6-8天的外周血单核细胞获得了将SHP-1募集到其CD46的能力，并同时能够生产IL-12 p40和一氧化氮（NO）。在同一时间范围内，Mφ获得了组装CD9的能力，Alphas betal整合素与CD46的能力。早期到该成熟阶段的Mφ能够潜在地位（Edmonston和Nagahata菌株）复制，但是在激活阶段，NO和细胞因子被诱导并严重抑制了MV复制。这些细胞反应是由C3B，C3B，MABS F（AB'）_ 2或MV H/F糖蛋白的直接连接，而不是细胞内MV复制。有趣的是，KO菌株在6-8天的GM-CSF培养Mφ中未能复制，而其他MV菌株在相同条件下复制以形成合成曲霉。当用KO应变刺激时，观察到SHP-1从CD46的快速和瞬时解离。综上所述，CD46首先用作MV的接收器，然后根据人Mφ的成熟阶段募集分子复合物。这些结果提供了有力的证据，表明CD46用作信号传递分子，并且配体的特性决定了先天免疫系统的抑制或激活。 MV介导的免疫抑制可能部分归因于CD46信号。