Evolutionary arms races in the battle for iron

描述（由申请人提供）：防止病原体获取必需铁是先天免疫的关键组成部分。因此，病原细菌已经发展出多种策略来从宿主蛋白质中清除铁。虽然感染中“铁之战”的重要性已广为人知，但这种冲突对宿主细胞途径的进化后果尚不清楚。在我的初步工作中，我发现一些铁隔离基因，包括铁转运蛋白转铁蛋白，在灵长类动物中迅速进化。值得注意的是，转铁蛋白中经历快速进化的密码子映射到与细菌转铁蛋白受体的相互作用位点，这表明转铁蛋白已经适应阻止病原体铁的获取。对于我的建议，我将对转铁蛋白和细菌受体进行系统发育分析，以识别受到强大进化压力的位点和谱系。我还将通过测试细菌在存在多种灵长类转铁蛋白同系物的情况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，这项工作将为涉及细菌病原体的分子军备竞赛提供首次详细分析，并揭示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.