Pathogenic effector protein modulation of host innate immune signaling

宿主先天免疫信号的致病效应蛋白调节

基本信息

批准号：
7511796
负责人：
RHEINALLT MELFYN JONES
金额：
$ 11.25万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-10 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7511796
关键词：
Aeromonas Affect Apoptosis Apoptotic Bacteria Biochemical Biochemical Genetics Biomedical Research Cells Commit Data Disease Doctor of Medicine Drosophila genus Drosophila inturned protein Enterocolitis Environment Epithelium Eye Family Genes Genetic Models Genetic Screening Goals Health Hemocytes Human Immune Immune response Infection Inflammatory Inflammatory Bowel Diseases Intestines Localized MAP Kinase Gene Mammals Mediating Mentors Mitogen-Activated Protein Kinase Kinases Modeling NFKB Signaling Pathway Natural Immunity Neutrophil Infiltration Outcome Pathway interactions Phagocytes Phenotype Principal Investigator Process Production Proteins Regulator Genes Resources Retinal Salmonella Scientist Score Signal Pathway Signal Transduction Specificity System Transgenic Organisms United States Vibrio Whole Organism Yersinia career cytokine enteric pathogen foodborne pathogen gastrointestinal epithelium genetic regulatory protein member novel pathogen protein expression response

项目摘要

DESCRIPTION (provided by applicant): Intestinal enterocolitis caused by food borne pathogens is a substantial health burden in the United States and internationally. Certain disease causing pathogens establish themselves within the host cells because they have evolved sophisticated mechanisms to evade host innate immunity. For example, pathogens secrete preformed effector proteins that influence innate immune and apoptotic signaling pathways thus inhibiting cytokine production, neutrophil recruitment, and/or activation of apoptosis. One group of bacterial effector proteins which usurp innate immune signaling is the AvrA-like family. These soluble proteins have potent inhibitory effects on the activation of the MARK and NF-kB signaling pathways, thereby modulating host inflammatory and apoptotic responses. This biochemical family is represented in multiple enteric pathogens including Salmonella, Yersinia, Vibrio and Aeromonas. We propose to 1) characterize the inhibitory profile of each AvrA-like protein using the Drosophila, a powerful genetic model which has functionally conserved innate immune and apoptotic pathways with mammals. We hypothesize that targeted blockade of distinct components of innate immune and apoptotic signaling controls differential effects on inflammatory or apoptotic outcomes in the whole organism. 2) We also propose to model the effects of AvrA-like proteins by their direct expression in the Drosophila gut epithelium, and in Drosophila hemocytes (which are analogous to human phagocytes) during pathogenic infection. We hypothesize that AvrA-like protein mediated inhibition of innate immune pathways localized to barrier epithelia or phagocytes facilitates pathogenic processes and untimely mediates the pathogenic outcome of infection by bacteria that secrete the particular AvrA-like protein. 3) Finally, we propose to use phenotypes resulting from the expression of AvrA-like proteins in Drosophila in a forward genetic screen for the discovery of novel innate immune and apoptotic regulatory genes. Together, these studies will further advance the understanding of the evasion strategies developed by enteric pathogens to escape the host immune response, and will contribute to our understanding of many intestinal inflammatory disorders. The candidate is committed to a career in biomedical research and his ultimate goal is to become an independent principal investigator in an academic setting. The rich environment provided by the support of his mentor, Dr Andrew Neish, M.D., his consultant Dr Kenneth Moberg, and a panel of eminent advisory scientists at Emory will provide the resources necessary to achieve his objectives.

描述（由申请人提供）：由食源性病原体引起的肠道小肠结肠炎是美国和国际上的一个重大健康负担。某些引起疾病的病原体在宿主细胞内定居，因为它们已经进化出复杂的机制来逃避宿主先天免疫。例如，病原体分泌预先形成的效应蛋白，影响先天免疫和细胞凋亡信号传导途径，从而抑制细胞因子产生、中性粒细胞募集和/或细胞凋亡激活。 AvrA 样家族是一组篡夺先天免疫信号的细菌效应蛋白。这些可溶性蛋白对 MARK 和 NF-kB 信号通路的激活具有有效的抑制作用，从而调节宿主炎症和细胞凋亡反应。该生化家族以多种肠道病原体为代表，包括沙门氏菌、耶尔森氏菌、弧菌和气单胞菌。我们建议 1) 使用果蝇来表征每种 AvrA 样蛋白的抑制谱，果蝇是一种强大的遗传模型，在哺乳动物中具有功能上保守的先天免疫和细胞凋亡途径。我们假设，有针对性地阻断先天免疫和细胞凋亡信号传导的不同成分可以控制对整个生物体炎症或细胞凋亡结果的不同影响。 2）我们还建议通过在病原体感染期间在果蝇肠道上皮和果蝇血细胞（类似于人类吞噬细胞）中的直接表达来模拟AvrA样蛋白的影响。我们假设 AvrA 样蛋白介导的对位于屏障上皮或吞噬细胞的先天免疫途径的抑制促进了致病过程，并不合时宜地介导了分泌特定 AvrA 样蛋白的细菌感染的致病结果。 3)最后，我们建议利用果蝇中AvrA样蛋白表达产生的表型进行正向遗传筛选，以发现新的先天免疫和凋亡调节基因。总之，这些研究将进一步增进对肠道病原体为逃避宿主免疫反应而开发的逃避策略的理解，并将有助于我们对许多肠道炎症性疾病的理解。候选人致力于生物医学研究事业，他的最终目标是成为学术环境中的独立首席研究员。他的导师、医学博士安德鲁·尼什博士、他的顾问肯尼思·莫伯格博士以及埃默里大学的杰出咨询科学家小组的支持所提供的丰富环境将为他实现目标提供必要的资源。