The sequestration of essential metals by host proteins provides an innate immune defense termed nutritional immunity. Microbial pathogens in turn meet their metabolic requirements by stealing these nutrients from the host. Recently we discovered that the primate bloodstream iron transporter, transferrin, has been engaged in a longstanding evolutionary conflict with transferrin binding protein A (TbpA), a major virulence factor in Gram-negative bacteria that scavenges iron from transferrin. Single mutations at rapidly evolving sites in transferrin and TbpA are sufficient to dictate this protein-protein interaction, providing a direct link between signatures of positive selection and pathogen receptor function. Moreover, we find that an abundant transferrin human polymorphism confers resistance to binding by H. influenzae TbpA, suggesting functional implications for transferrin evolution in modern humans. Together this work establishes the “battle for iron” as a critical node of host-pathogen evolutionary conflict, on par with those involving canonical host immunity factors. More recently we have identified new evidence for positive selection involving primate nutritional immunity factors beyond
transferrin. We are continuing to investigate the genetic and biochemical basis of these host-pathogen conflicts as well as implications for human disease.