Functional and evolutionary genomics of host adaptation

宿主适应的功能和进化基因组学

• 批准号: 227673-2009
• 负责人: Guttman, David
• 金额: $ 6.41万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=524056
• 关键词: Functional; evolutionary; genomics; host; adaptation

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.

病原体与其宿主不断地进行无情且往往致命的斗争，这种斗争是由病原体侧的多种毒力因子以及宿主侧的监视和防御系统介导和调节的。表征这些因素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、新颖且稳健的方法，用于识别和表征可以说是影响疾病和防御的两个最重要因素：病原体相关分子模式 (PAMP) 和 III 型分泌效应蛋白 (T3SE)。 PAMP 是被植物和动物细胞上的受体识别并诱导免疫或防御反应的微生物因子。 T3SE 是注入宿主细胞的细菌蛋白，可破坏这些免疫反应的诱导。我们开发了 PAMP 屏幕，它已经极大地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 库存，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 T3SE 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所起的作用。重要的是，这项研究将为研究任何系统中的 PAMP 提供一个非常通用的框架，并特别建议为这些研究开发一个通用工具。本研究中确定的 PAMP 有潜力用作新型抗菌剂，因为它们可以以多种不同的形式部署，并以非常特定的方式诱导免疫。该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点。我们将鉴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大大加深对影响先天免疫的因素的理解，这些因素会立即影响我们的健康、食物供应和环境。