Functional and evolutionary genomics of host adaptation

病原体及其宿主不断进行无情且往往致命的斗争，病原体方面的各种毒力因子以及宿主方面的监测和防御系统介导和调节。确定这些因素的特征对于理解和控制疾病至关重要。该提案描述了一种雄心勃勃的，新颖的和强大的手段来识别和表征可以说是影响疾病和防御的两个最重要的因素：病原体相关分子模式（PAMP）和III型分泌效应蛋白（T3 SE）。PAMP是由植物和动物细胞上的受体识别的微生物因子，并且其诱导免疫或防御反应。T3 SE是注射到宿主细胞中以破坏这些免疫应答的诱导的细菌蛋白。我们已经开发了一种PAMP屏幕，它已经大大增加了我们对这些重要分子的广度和性质的理解。拟议的工作将进一步完善我们的PAMP清单，明确识别识别每个PAMP的宿主防御受体套件，追踪防御信号网络以确定其多样性，特异性和相互依赖性，确定这些防御信号通路对T3 SE破坏的敏感程度，然后评估PAMP等位基因之间的自然变异在影响宿主特异性相互作用中的作用。重要的是，这项研究将提供一个非常一般的框架，研究PAMP在任何系统中，并特别提出开发一个通用的工具，这些研究。本研究中鉴定的PAMP具有用作新型抗菌剂的潜力，因为它们可以以一系列不同的形式部署，并以非常特异的方式诱导免疫。这项研究将利用共同进化过程已经完成的艰苦工作来揭示防御信号网络中的“薄弱环节”-防御网络中最容易受到病原体攻击的那些点。我们将确定针对这些薄弱环节的细菌毒力蛋白。这些研究的最终结果将是大大增强对影响先天免疫的因素的理解-这些因素直接影响我们的健康，我们的食物供应和我们的环境。

Pathogens and their hosts continuously engage in a relentless and often deadly struggle mediated and modulated by diverse suites of virulence factors on the pathogen side, and surveillance and defense sys-tems on the host side. Characterizing these factors is central to understanding and controlling disease. This proposal describes an ambitious, novel, and robust means to identify and characterize what are arguably the two most significant factors influencing disease and defense: pathogen-associated molecular patterns (PAMPs) and type III secreted effector proteins (T3SEs). PAMPs are microbial factors that are recognized by receptors on plant and animal cells, and which induce immune or defense responses. T3SEs are bacterial proteins injected into host cells to disrupt the induction of these immune responses. We have developed a PAMP screen which has already dramatically increased our understanding of the breadth and nature of these important molecules. The proposed work will further refine our inventory of PAMPs, clearly identify the suite of host defense receptors that recognize each PAMP, trace the defense signaling networks to determine their variety, specificity, and interdependence, determine how sensitive these defense signaling pathways are to disruption by T3SEs, and then assess the role that natural variation among PAMP alleles plays in influencing host specific interactions. Importantly, this study will provide a very general framework for studying PAMPs in any system, and specifically proposes to develop a general tool for these studies. The PAMPs identified in this study have the potential to be used as novel antimicrobial agents as they can be deployed in a range of different formats, and induce immunity in very specific ways. The study will take advantage of the hard work already done by co-evolutionary process to reveal the 'weak links' in defense signaling networks - those points in the defense network most vulnerable to pathogen attack. We will identify the bacterial virulence proteins that target these weak links. The net result of these studies will be a vastly enhanced understanding of the factors that influence innate immunity - factors that immediately impact our health, our food supply, and our environment.