CD46 as a Signaling Intermediate in N. gonorrhoeae Infection

CD46 作为淋病奈瑟菌感染中的信号传导中间体

• 批准号: 7849990
• 负责人: MAGDALENE Y SO
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849990
• 关键词: Adenoviruses; Affect; Bacteria; Biological; Biology; CD46 Antigen; Cell Line; Cells; Cleaved cell; Complex; Cytoplasmic Tail; Epithelial Cells; Goals; Human; Immune; Infection; Inflammation; Knowledge; Lead; Light; Matrix Metalloproteinases; Membrane Proteins; Methods; Modeling; Molecular; Neisseria; Neisseria gonorrhoeae; Neisseria meningitidis; Outcome; Pathway interactions; Peptide Hydrolases; Phenotype; Phosphorylation; Pilum; Positioning Attribute; Process; Property; Protein Isoforms; Proteins; Proteolytic Processing; Publishing; Receptor Signaling; Regulation; Relative (related person); Role; Signal Transduction; Signaling Protein; Streptococcus pyogenes; Tail; Testing; Virus; abstracting; immune function; knowledge base; man; microbial; mutant; pathogen; presenilin; receptor; secretase; trafficking

Abstract CD46 is a human-specific immunoregulatory protein with signaling and receptor properties in immune cells. Activation of CD46 can lead to a variety of outcomes, ranging from immune regulation to inflammation, depending on the relative levels of the two isoforms. Several viruses and bacteria target CD46 during infection, using it as a receptor or downregulating it in infected cells. N. gonorrhoeae (Ng) interacts with epithelial cell CD46 at multiple levels. Infection via the Type IV pilus directly or indirectly triggers its phosphorylation, alters its trafficking, and causes its secretion. Although is published on the numerous biological phenotypes associated with CD46, little is known about the molecular mechanisms underlying them. We have obtained compelling evidence that the pathogenic Neisseria, N. gonorrhoeae and N. meningitidis, stimulate CD46 processing by Presenilin/¿-Secretase (PS), a protease complex that regulates many important signaling proteins. Our goal is to understand how Presenilin/¿-Secretase processing of CD46 affects its signaling activities of host cells, and how these activities relate to infection. We propose a model for this CD46 processing pathway and we propose to test the predictions from this model. We are uniquely positioned for these studies with our tail-specific mAbs and the Presenilin double negative mutant cell line. Our studies will shed light on the host aspect of Neisseria biology. Our findings will also add to the knowledge base of CD46 function, and hopefully shed light on other pathogens/CD46 interactions.

摘要 CD 46是一种人特异性免疫调节蛋白，在免疫应答中具有信号传导和受体特性。 细胞CD 46的激活可导致多种结果，从免疫调节到免疫抑制， 炎症，这取决于两种亚型的相对水平。几种病毒和细菌的目标 CD 46在感染过程中，使用它作为受体或在感染细胞中下调它。N.淋病（Ng） 与上皮细胞CD 46在多个水平相互作用。通过IV型菌毛直接或间接感染 触发其磷酸化，改变其运输，并导致其分泌。 尽管发表了许多与CD 46相关的生物学表型， 了解它们背后的分子机制。我们已经获得了有力的证据 致病性奈瑟氏菌、N.淋病奈瑟菌和淋病奈瑟菌。脑膜炎，刺激CD 46处理， 早老素/β-分泌酶（PS），一种调节许多重要信号蛋白的蛋白酶复合物。 我们的目标是了解CD 46的早老素/β-分泌酶加工如何影响其信号传导 宿主细胞的活动，以及这些活动与感染的关系。我们为此提出了一个模型 CD 46处理途径，我们建议测试这个模型的预测。我们是唯一 我们的尾特异性mAb和早老素双阴性突变体定位于这些研究 细胞系我们的研究将阐明奈瑟菌生物学的宿主方面。我们的发现也将 增加了CD 46功能的知识基础，并有望阐明其他病原体/CD 46 交互.