Project Summary Microbes and their animal hosts encode numerous proteins to sense, manipulate, and defend against each other. The outcome of these interactions can mean the difference between a mutualistic exchange and a fatal infection. Epithelial surfaces provide the point of first contact between hosts and diverse communities of commensal bacteria, in addition to forming a critical barrier against bacterial pathogens. Although host and microbial proteins at these interfaces can evolve rapidly between and within populations, the impact of such diversity on immune defense is largely unknown. This proposal will leverage host-microbe barrier interactions as models to investigate the causes and consequences of adaptive protein evolution. We will first apply integrative phylogenetic and experimental approaches to determine how diversification of epithelial surface proteins mediates cell-cell adhesion and virulence of human-associated bacterial pathogens. In a second line of study, we will identify how evolution of primate secreted immunity proteins modulates bacterial destruction and defense functions. These projects will also employ experimental evolution in the laboratory to trace mechanisms of bacterial adaptation to antimicrobial enzymes in real time. This research program will advance our fundamental understanding of evolving host-microbe systems and accelerate strategies to diagnose and combat the growing threat of bacterial infectious disease.