ROLE OF CD46 IN MEASLES ENTRY AND IMMUNOSUPPRESSION

CD46 在麻疹进入和免疫抑制中的作用

• 批准号: 6752053
• 负责人: MARIANNE MANCHESTER
• 金额: $ 31.06万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752053
• 关键词: CD antigens; biological signal transduction; cell surface receptors; clinical research; genetically modified animals; human subject; immunosuppression; laboratory mouse; measles virus; microorganism immunology; virus infection mechanism

DESCRIPTION: (Adapted from the Investigator's abstract): Despite an effective vaccine, measles virus (MV) is still the seventh leading cause of death worldwide. MV causes significant morbidity an mortality due to virus-associated immunosuppression and kills over 1 million children per year. Why is measles still a public health problem when a vaccine is available? The extremely infectious nature of the virus interference with MV vaccination by maternally-acquired antibodies, and waning immunity in vaccines all contribute to the stubborn resistance of MV to eradication. The interaction between viruses and cell-surface receptors is a major determinant of virus tropism an pathogenesis. For MV, the cell-surface receptor has been identified as the complement receptor CD46. The normal function of CD46 is to bind complement components on the cell surface and prevent their deposition on host cells. Previous studies have shown that complement C3b, the primary ligand for CD46 interacts with regions of the extracellular domain of CD46 near the membrane. Laboratory strains of MV, in contrast, interact with the N-terminal third of the extracellular domain of CD46. This interaction not only results in MV attachment and entry, but can also signal target lymphocytes to downregulate cytokine production. The long range goal of this project, is to determine how wild-type MV interacts with the MV receptor CD46 to result in host-cell attachment, entry and modulation on intracellular signaling. First, emphasis is placed on mapping the specific interaction between wild-type strains of MV and the extracellular domain of the CD46 receptor. A combined molecular genetic and structural analysis will be used to identify and characterize the domain of the CD46 receptor that are responsible for interacting with wild-type MV to achieve virus binding, entry an immunosuppressive effects in target host cells. A second emphasis of this grant is to characterize the signaling events that occur upon liganding of CD46 by wild-type and laboratory strains of MV and how these events regulate virus entry and immune function. Determining how the interaction between MV and CD46 influences intracellular signals is important not only for understanding how measles-induced immunosuppression occurs, but provides a potential tool for studying how virus-receptor interactions can modulate host cell functions.

描述：(改编自调查人员摘要)：尽管 疫苗，麻疹病毒(MV)仍然是第七大致死原因 全世界。MV因病毒相关导致显著的发病率和死亡率 每年有100多万儿童死于免疫抑制。为什么麻疹 当疫苗可用时，仍然是一个公共卫生问题吗？极致的 病毒的传染性对MV疫苗接种的干扰 母体获得的抗体和疫苗中免疫力的减弱都起到了作用 对根治MV的顽强抵抗。两国之间的相互作用 病毒和细胞表面受体是病毒嗜性和 发病机制。对于MV，细胞表面受体已被鉴定为 补体受体CD46。CD46的正常功能是结合补体 在细胞表面，防止它们沉积在宿主细胞上。 先前的研究表明，补体C3b是CD46的主要配体 与CD46胞外区靠近膜的区域相互作用。 相比之下，实验室的MV毒株与N端的三分之一相互作用 CD46的胞外区。这种相互作用不仅导致MV 附着和进入，但也可以向靶淋巴细胞发出下调信号 细胞因子的产生。该项目的长期目标是确定如何 野生型MV与MV受体CD46相互作用产生宿主细胞 细胞内信号的附着、进入和调制。首先，重点是 放在定位MV野生型株系和野生型毒株之间的特异性相互作用上 CD46受体的胞外区。一种结合了分子遗传学和 将使用结构分析来确定和表征 负责与野生型MV相互作用的CD46受体实现 病毒结合，进入靶宿主细胞产生免疫抑制作用。一个 这项资助的第二个重点是表征信号事件， MV野生型和实验室毒株与CD46连接时发生的情况以及如何发生 这些事件调节病毒进入和免疫功能。确定如何 MV和CD46之间的相互作用影响细胞内信号是重要的 不仅是为了了解麻疹诱导的免疫抑制是如何发生的，而且 提供了一个潜在的工具来研究病毒-受体相互作用如何 调节宿主细胞的功能。