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，病原体分泌预先形成的效应蛋白，影响先天免疫和凋亡信号通路，从而抑制细胞因子的产生、中性粒细胞的募集和/或细胞凋亡的激活。一组侵占先天免疫信号的细菌效应蛋白是Avra样家族。这些可溶性蛋白对MARK和NF-kB信号通路的激活有很强的抑制作用，从而调节宿主的炎症和凋亡反应。这个生化家族存在于多种肠道病原体中，包括沙门氏菌、耶尔森氏菌、弧菌和气单胞菌。我们建议1)使用果蝇来表征每个Avra样蛋白的抑制谱，果蝇是一种强大的遗传模型，它在功能上保守了哺乳动物的先天免疫和凋亡途径。我们假设，靶向阻断先天免疫和凋亡信号的不同成分控制着对整个生物体中炎症或凋亡结果的不同影响。2)我们还建议通过在果蝇肠道上皮和果蝇血细胞(类似于人的吞噬细胞)中直接表达Avra样蛋白来模拟其在病原性感染过程中的作用。我们假设，Avra样蛋白介导了对屏障上皮或吞噬细胞固有免疫途径的抑制，促进了致病过程，并过早地介导了分泌特定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样蛋白的表达所产生的表型来进行正向遗传筛选，以发现新的先天免疫和凋亡调节基因。综上所述，这些研究将进一步促进对肠道病原体为逃避宿主免疫反应而制定的逃避策略的理解，并将有助于我们对许多肠道炎症性疾病的理解。这位候选人致力于生物医学研究，他的最终目标是成为一名学术背景下的独立首席研究员。他的导师Andrew Neish医学博士、他的顾问Kenneth Moberg博士和埃默里著名顾问科学家小组的支持提供的丰富环境将为实现他的目标提供必要的资源。

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.