Mechanisms of evolution at the host-pathogen interface

PROJECT SUMMARY Pathogens and their hosts impose strong selective pressure on one another, leading to the rapid evolution of host-pathogen molecular interactions. This process in turn can shape pathogen host range, virulence, and the emergence or reemergence of infectious diseases in human populations. These features also make host-pathogen interactions ideal systems to investigate fundamental evolutionary processes including natural selection and the diversification of protein functions. While comparative and population genomic datasets are now plentiful for many pathogens and animals, empirical studies are required in order to test how specific genetic variants impact disease-related phenotypes. To meet this need, our research group integrates evolutionary genetics with molecular approaches to investigate the mechanisms and consequences of host-pathogen evolution. Our work focuses on bacterial pathogens of humans, a leading cause of death worldwide and a growing source of antimicrobial resistant infections. Using phylogenetic methods to identify rapidly-evolving genes in both host and bacterial genomes, we develop and test hypotheses regarding the effects of genetic variation using a combination of biochemistry, molecular genetics, cell biology, and laboratory microbiology. Our group has leveraged this integrative framework over the last several years to initiate diverse projects relating to bacterial colonization, nutrient acquisition, and immune evasion. Future studies performed under this award will advance two general research areas. The first will investigate how rapid evolution of animal and bacterial cell surface receptors impacts colonization and immune evasion. These studies build from our recent findings illustrating how combinatorial processes of substitution, gene conversion, and gene duplication contribute to bacterial-host receptor interactions. The second research area will address how rapid evolution of host antimicrobial enzymes impacts activity against diverse bacterial pathogens, as well as processes by which pathogens have evolved to evade these enzymes. Specific projects under these research areas encompass diverse molecular interactions and multiple bacterial pathogens, amenable to long-term investigation. Collectively this research program will uncover key mechanisms and consequences of host-pathogen evolution to inform new strategies for combatting bacterial infections.