Adaptive evolution of bacteria in the battle for iron

 描述(申请人提供)：微生物病原体和它们的宿主之间的进化相互作用可能意味着致命的大流行和轻微感染之间的区别。铁和其他微量营养素的封存最近已经成为一种被称为营养免疫的强大的固有宿主防御形式，这种免疫被病原体“盗铁”积极地抵消，以从宿主蛋白中清除这种营养。虽然这些相互作用的分子基础已经确立，但之前还没有人研究过“铁之战”的进化含义。我最近发现，灵长类铁运输蛋白转铁蛋白与细菌表面受体TbpA之间存在长期的进化冲突。TbpA是一种细菌表面受体，以转铁蛋白为目标，作为一种营养铁源。实验证据进一步表明，转铁蛋白进化在灵长类动物4000万年的分化过程中发挥了重要作用，甚至在现代人类群体中也发挥了重要作用。这项建议旨在用微生物学和基因组学方法补充我过去在生物化学和进化遗传学方面的培训，以转铁蛋白-TbpA界面作为模型系统，研究细菌病原体进化的机制。在这个奖项的K99阶段，我将使用分子遗传学和细菌竞争分析来研究细菌TbpA快速进化的功能后果。这项工作将补充实验进化方法，使用转铁蛋白-TbpA接口来研究进化权衡和病原体宿主范围，我将把这项工作带入该奖项的独立R00阶段。这一提议将为一项整合进化遗传学、生物化学和微生物学的独立研究计划奠定基础，以调查宿主-病原体进化对人类健康和疾病易感性的影响。

 DESCRIPTION (provided by applicant): Evolutionary interactions between microbial pathogens and their hosts can mean the difference between a deadly pandemic and minor infection. The sequestration of iron and other micronutrients has recently emerged as a potent form of innate host defense termed nutritional immunity, which is actively counteracted by pathogen "iron piracy" to scavenge this nutrient from host proteins. While the molecular basis for these interactions have been established, the evolutionary implications of the "battle for iron" have not been previously investigated. I recently discovered that the primate iron transport protein transferrin has been engaged in a long- standing evolutionary conflict with TbpA, a bacterial surface receptor that targets transferrin as a nutrient iron source. Experimental evidence further indicates that transferrin evolution has played an important role during 40 million years of primate divergence and even in modern human populations. This proposal aims to complement my past training in biochemistry and evolutionary genetics with microbiology and genomic approaches to investigate mechanisms of bacterial pathogen evolution, using the transferrin-TbpA interface as a model system. During the K99 phase of this award I will investigate the functional consequences for rapid evolution in bacterial TbpA using molecular genetics as well as bacterial competition assays. This work will complement experimental evolution approaches using the transferrin-TbpA interface to study evolutionary trade-offs and pathogen host-range, work which I will carry forward into the independent R00 stage of the award. Together this proposal will lay the groundwork for an independent research program that integrates evolutionary genetics, biochemistry and microbiology to investigate the implications of host-pathogen evolution on human health and disease susceptibility.