Evolutionary arms races in the battle for iron

说明(申请人提供)：防止病原体获得必需的铁是先天免疫的重要组成部分。因此，病原菌开发了各种策略来从宿主蛋白中清除铁。虽然“铁之战”在感染中的重要性得到了很好的理解，但这种冲突在宿主细胞途径上的进化后果尚不清楚。在我的初步工作中，我发现了几个铁储存基因，包括铁转运蛋白，在灵长类动物中正在迅速进化。值得注意的是，正在经历快速进化的转铁蛋白中的密码子映射到与细菌转铁蛋白受体相互作用的位置，表明转铁蛋白已经适应了阻止病原体铁的获取。在我的提案中，我将对转铁蛋白和细菌受体进行系统发育分析，以确定受到强大进化压力的位置和谱系。我还将通过测试细菌在不同灵长类转铁蛋白同源物存在下的生长来确定转铁蛋白适应的功能后果。最后，我将评估与病原体驱动的转铁蛋白内源性功能进化相关的权衡，包括铁结合和与人类受体的相互作用。总之，这项工作将提供涉及细菌病原体的分子军备竞赛的首批详细分析之一，并阐明病原体如何塑造基本宿主细胞途径的进化。

DESCRIPTION (provided by applicant): Preventing the acquisition of essential iron by pathogens is a critical component of innate immunity. Pathogenic bacteria have thus developed various strategies to scavenge iron from host proteins. While the importance of the "battle for iron" in infection is well appreciated, the evolutionary consequences for this conflict on host cellular pathways are unknown. In my preliminary work I have found that several iron sequestration genes, including the iron transporter transferrin, are rapidly evolving in primates. Notably, codons in transferrin undergoing rapid evolution map to interaction sites with bacterial transferrin receptors, suggesting that transferrin has adapted to thwart pathogen iron acquisition. For my proposal I will perform phylogenetic analyses of transferrin and bacterial receptors to identify sites and lineages subject to strong evolutionary pressure. I will also determine the functional consequences of transferrin adaptation by testing bacterial growth in the presence of diverse primate transferrin homologs. Finally, I will assess the trade-offs associated with pathogen- driven evolution on transferrin endogenous functions, including iron binding and interaction with human receptors. Together, this work will provide one of the first detailed analyses of a molecular arms race involving bacterial pathogens and shed light on how pathogens have shaped the evolution of a fundamental host cellular pathway.