Adaptive evolution of bacteria in the battle for iron

 描述（由申请人提供）：微生物病原体及其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差异。铁和其他微量营养素的封存最近成为宿主先天防御的一种有效形式，称为营养免疫，它会被病原体“铁掠夺”积极抵消，以从宿主蛋白质中清除这种营养素。虽然这些相互作用的分子基础已经建立，但“铁之战”的进化意义以前尚未研究过。我最近发现，灵长类动物铁转运蛋白转铁蛋白一直在与TbpA进行长期的进化冲突，TbpA是一种细菌表面受体，靶向转铁蛋白作为营养铁源。实验证据进一步表明，转铁蛋白的进化在4000万年的灵长类分化过程中，甚至在现代人类种群中发挥了重要作用。该提案旨在补充我过去在生物化学和进化遗传学方面的培训，采用微生物学和基因组方法，以转铁蛋白-TbpA界面为模型系统，研究细菌病原体进化的机制。在该奖项的K99阶段，我将使用分子遗传学以及细菌竞争试验研究细菌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接口研究进化权衡和病原体宿主范围，我将把这项工作推进到该奖项的独立R 00阶段。这项提案将为一个独立的研究计划奠定基础，该计划将进化遗传学，生物化学和微生物学相结合，以研究宿主-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.