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: 6374360
• 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6374360
• 关键词: CD antigens; biological signal transduction; 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：（改编自研究者摘要）：尽管有效 麻疹病毒（MV）仍然是第七大死亡原因 国际吧MV引起显著的发病率和死亡率， 免疫抑制，每年杀死100多万儿童。为什么是麻疹 当疫苗可用时，这仍然是一个公共卫生问题？极 病毒干扰MV疫苗接种的传染性， 母亲获得的抗体，以及疫苗免疫力的减弱， 到MV对根除的顽固抵抗。之间的相互作用 病毒和细胞表面受体是病毒嗜性的主要决定因素， 发病机制对于MV，细胞表面受体已被确定为 补体受体CD 46。CD 46的正常功能是结合补体， 细胞表面上的组分，并防止其沉积在宿主细胞上。 以前的研究表明，补体C3 b，CD 46的主要配体， 与膜附近的CD 46胞外结构域区域相互作用。 相反，MV的实验室菌株与N-末端三分之一的 CD 46的胞外区。这种相互作用不仅导致MV 附着和进入，但也可以信号靶淋巴细胞下调 细胞因子产生。这个项目的长期目标是确定如何 野生型MV与MV受体CD 46相互作用， 附着、进入和调节细胞内信号传导。首先，重点是 放置在映射之间的特异性相互作用的野生型菌株的MV和 CD 46受体的胞外区。一种结合了分子遗传学和 结构分析将用于识别和表征的域的 CD 46受体，负责与野生型MV相互作用以实现 病毒结合，进入靶宿主细胞的免疫抑制作用。一 该授权的第二个重点是表征 在野生型和实验室MV菌株与CD 46配位后发生，以及如何 这些事件调节病毒进入和免疫功能。确定如何 MV和CD 46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， 为研究病毒-受体相互作用如何 调节宿主细胞功能。