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，对感染性病原体致病机制的理解已经发生了革命性的变化。进化生物学家还为我们对传染病动力学的理解提供了重要的见解，包括毒力的进化。尽管自然界中的寄主同时受到多个病原体和寄生虫的攻击，但由于大多数研究集中在单一病原体上，分子生物学家很少研究这种相互作用。相反，尽管生物学家研究这些相互作用的目的是为了揭示宿主-寄生虫相互作用的生态学和进化的一般原理，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表征。因此，公共卫生研究人员加入了进化生物学家的行列，努力更好地了解和控制传染病。本研究旨在研究拟南芥、丁香假单胞菌和食草性昆虫三向致病系统中病原菌对两种类型的寄主防御信号调控的最近(遗传/生理/机制)和最终(进化)机制。PS操纵防御信号串扰，导致对相同病原体感染的系统诱导敏感性(SIS)，并增加对草食性疾病的抗性或敏感性(SIS)。SIS对Ps的调节是由强毒Ps产生的茉莉酸类似物冠菌素(COR)介导的。然而，调节SIS到食草性的信号是未知的，在这两种情况下，寄主植物中支持系统信号的基因也是未知的。在第一个目标中，我将建立在初步的基因表达实验的基础上，以表征这两种类型SIS的潜在途径。在第二个目标中，我将通过亲缘选择、载体能力和其他实验来考察这两种类型的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好理解。保守的防御信号通路、先天免疫和许多其他适用于所有寄主-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，了解SIS对强毒Ps和草食反应的遗传、生理和进化基础，从而了解毒力的发病机制和进化，直接关系到NIH的使命。

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.