Pathogenic effector protein modulation of host innate immune signaling

描述（由申请人提供）： 由食源性病原体引起的小肠结肠炎在美国和国际上是一个巨大的健康负担。某些引起疾病的病原体在宿主细胞内建立自己，因为它们已经进化出复杂的机制来逃避宿主的先天免疫。例如，病原体分泌影响先天免疫和凋亡信号传导途径的预先形成的效应蛋白，从而抑制细胞因子产生、嗜中性粒细胞募集和/或凋亡活化。一组篡夺先天免疫信号传导的细菌效应蛋白是AvrA样家族。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，从而调节宿主的炎症和凋亡反应。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（Drosophila）表征每个AvrA样蛋白的抑制谱，果蝇是一种功能上保守的哺乳动物先天免疫和凋亡途径的强大遗传模型。我们假设，先天免疫和凋亡信号传导的不同组分的靶向阻断控制了整个生物体中炎症或凋亡结果的差异效应。2)我们还提出了模型的AvrA样蛋白的影响，其直接表达在果蝇肠道上皮细胞，并在果蝇血细胞（这是类似于人类的吞噬细胞）在病原体感染。我们假设，AvrA样蛋白介导的抑制先天免疫途径定位于屏障上皮细胞或吞噬细胞促进致病过程和不合时宜的介导的致病结果的细菌分泌特定的AvrA样蛋白的感染。3)最后，我们建议使用表型的AvrA样蛋白在果蝇中的表达，在一个向前的遗传筛选发现新的先天免疫和凋亡调控基因。总之，这些研究将进一步推进肠道病原体逃避宿主免疫反应的逃避策略的理解，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的职业生涯，他的最终目标是成为学术环境中的独立首席研究员。在他的导师安德鲁·尼什博士的支持下，他的顾问肯尼思·莫伯格博士和埃默里大学的一个著名顾问科学家小组将提供必要的资源来实现他的目标。

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.