Evolutionary arms races in the battle for iron

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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.