Dissecting Mechanisms of Host Manipulation by Pathogens

描述（由申请人提供）：通过使用模型遗传系统，特别是在植物病原体的情况下，理解感染因子引起疾病的机制已经发生了革命性的变化。进化生物学家也为我们理解传染病动力学提供了重要的见解，包括毒力的进化。尽管自然界中的宿主同时受到多种病原体和寄生虫的攻击，但这种相互作用很少被分子生物学家研究，因为大多数研究都集中在单一病原体上。相反，尽管生物学家研究这些相互作用的目的是揭示宿主-寄生虫相互作用的生态学和进化的一般原则，但由宿主防御反应介导的生物相互作用的潜在遗传或机制基础很少被描述。因此，公共卫生研究人员与进化生物学家一起努力更好地了解和控制传染病。该提案提出了实验设计，以表征近（遗传/生理/机械）和最终（进化）机制的两种类型的主机防御信号操纵的病原体在一个模型的三向病理系统，涉及拟南芥，病原体假单胞菌（PS）和昆虫草食动物。PS操纵防御信号串扰，导致对相同病原体感染的系统诱导易感性（SIS）和对草食动物的增加的抗性或易感性（SIS）。SIS到Ps是由茉莉酸类似物冠菌素（COR）介导的，它是由有毒的Ps产生的。然而，信号介导的SIS植食性是未知的，在这两种情况下，在宿主植物中的系统性信号的基因是未知的。在第一个目标中，我将建立在初步的基因表达实验，以表征这两种类型的SIS的潜在途径。在第二个目标中，我将通过亲属选择、向量胜任力等实验来考察这两种SIS是否存在适应性基础。每个目标都与共同发起人的研究和我的长期职业目标相吻合。植物-病原体系统的发现直接导致了对人类-病原体相互作用的更深入理解。保守的防御信号通路，先天免疫和许多其他适用于所有宿主-病原体相互作用的见解始于对植物及其病原体的研究。因此，理解SIS对有毒Ps和草食动物的反应的遗传、生理和进化基础，以理解致病机理和毒力进化为目标，与NIH的使命直接相关。

DESCRIPTION (provided by applicant): Understanding the mechanisms by which infectious agents cause disease has been revolutionized through the use of model genetic systems, especially in the case of plant pathogens. Evolutionary biologists have also provided significant insight into our understanding of infectious disease dynamics, including the evolution of virulence. Although hosts in nature are attacked by multiple pathogens and parasites simultaneously, such interactions are rarely studied by molecular biologists since most studies focus on a single pathogen. Conversely, although organismal biologists study these interactions with the goal of uncovering general principles underlying the ecology and evolution of host-parasite interactions, the underlying genetic or mechanistic bases of the biotic interactions mediated by host defense responses are rarely characterized. Thus, public health researchers have joined with evolutionary biologists in an effort to better understand and control infectious diseases. This proposal presents experiments designed to characterize proximate (genetic/physiological/mechanistic) and ultimate (evolutionary) mechanisms underlying two types of host defense signaling manipulation by pathogens in a model three-way pathosystem involving Arabidopsis, the pathogen Pseudomonas syringae (Ps) and insect herbivores. Ps manipulates defense signaling cross talk leading to systemic induced susceptibility (SIS) to infection by the same pathogens and increased resistance or susceptibility (SIS) to herbivory. SIS to Ps is mediated by the jasmonic acid analog coronatine (COR), which is produced by virulent Ps. However, the signal mediating the SIS to herbivory is unknown, and in both cases, the genes underlying systemic signals in the host plant are unknown. In the first aim, I will build on preliminary gene expression experiments to characterize the pathways underlying both types of SIS. In the second aim, I will investigate whether there is an adaptive basis to the two types of SIS by conducting kin selection, vector competency and other experiments. Each aim dovetails with the cosponsors' research and my long-term career goals. Discoveries from plant- pathogen systems have led directly to a greater understanding of human-pathogen interactions. Conserved defense signaling pathways, innate immunity and many other insights that apply to all host-pathogen interactions began with studies of plants and their pathogens. Understanding the genetic, physiological and evolutionary basis of the SIS response to virulent Ps and herbivory with the goal of understanding pathogenesis and evolution of virulence is therefore directly related to the mission of the NIH.