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Molecular mechanism of measles virus-induced immunosuppression

麻疹病毒诱导免疫抑制的分子机制

基本信息

批准号：
06670322
负责人：
YANAGI Yusuke
金额：
$ 1.34万
依托单位：
Kyusyu University (1995)The University of Tokyo (1994)
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06670322/
关键词：
Measles virus Immunosuppression CD46 麻疹ウイルスレセプター細胞融合

项目摘要

Mouse fibroblast cell lines (L, NIH3T3) supported a low level of measles virus (MV) replication. These fibroblasts never formed multinucleated giant cells, a characteristic cytopathic effect of MV infection. We derived L cell transfectants stably expressing the gene encoding the human CD46, the recently identified MV receptor. Upon infection with MV, these transfectants produced 20 fold more MV, became 100 time more sensitive to MV than the parental L cells, and developed syncytia. To determine the domain (s) in CD46 essential for the receptor function, several deletion mutants were generated that lacked the cytoplasmic region or each one of the four short consensus repeat (SCR) of CD46. Mutants lacking SCR1 or SCR2 were found not to act as the receptor, indicating that SCR1 or SCR2 are indispensable for the function as the MV receptor. On the basis of these results, we produced transgenic mice expressing the human CD46 as an animal model to study immunosuppression observed during MV infection. We are currently testing whether these mice are susceptible to MV, and develop any clinical signs.We also examined the mechanism by which MV inhibitits thein vitro proliferation of T cells. Coculture with cells expressing MV glycoproteins without producing infectious MV did not lead to the inhibition of the mitogen-induced T cell proliferation, indicating that the cell-cell interaction through MV glycoproteins expressed on MV-infected cells and surface molecules on uninfected cells is not sufficient to cause the inhibition of T cell proliferation.

小鼠成纤维细胞系（L，NIH3T3）支持低水平的麻疹病毒（MV）复制。这些成纤维细胞从未形成多核巨细胞，这是MV感染的特征性细胞病变效应。我们衍生出稳定表达编码人类 CD46 的基因的 L 细胞转染子，CD46 是最近发现的 MV 受体。感染 MV 后，这些转染子产生的 MV 多 20 倍，对 MV 的敏感性比亲本 L 细胞高 100 倍，并形成合胞体。为了确定 CD46 中对受体功能至关重要的结构域，产生了几种缺失突变体，它们缺乏细胞质区域或 CD46 的四个短共有重复序列 (SCR) 中的每一个。发现缺乏SCR1或SCR2的突变体不能充当受体，这表明SCR1或SCR2对于MV受体的功能是不可或缺的。基于这些结果，我们制备了表达人CD46的转基因小鼠作为动物模型来研究MV感染期间观察到的免疫抑制。我们目前正在测试这些小鼠是否对 MV 敏感，并出现任何临床症状。我们还研究了 MV 抑制 T 细胞体外增殖的机制。与表达MV糖蛋白而不产生感染性MV的细胞共培养不会导致对丝裂原诱导的T细胞增殖的抑制，表明通过MV感染细胞上表达的MV糖蛋白和未感染细胞上表面分子的细胞-细胞相互作用不足以引起T细胞增殖的抑制。