Project Summary/Abstract Helminths (i.e., parasitic worms) infect all vertebrate taxa. Hosts generally evolve to block, purge, or limit the negative effects of infection, and parasites evolve to hide from or manipulate host physiology. Numerous molecules and cellular pathways are known to modulate interactions between vertebrate hosts and helminth parasites, but little is known about how the evolution of immunity and infectivity influences natural variation in parasite infections. Data on the particular genetic differences that underlie evolved differences in immunity are similarly limited. Over the next five years, my lab will describe the genetic mechanisms and evolutionary history of coevolution between a small fish with abundant ecological and genetic resources, the threespine stickleback (Gasterosteus aculeatus), and one of its cestode parasites. This work is facilitated by lab-based protocols to efficiently intercross cestodes, expose sticklebacks to controlled doses of these pathogens, co-culture host and immune cells in vitro, and assays of host immunity and parasite viability. We can not only identify and measure heritable traits that affect infection specificity and intensity, but also apply modern genetic approaches to dissect the molecular mechanisms underlying this naturally selected variation. Our preliminary data show that threespine sticklebacks repeatedly evolved to block the initial establishment and subsequent growth of cestodes, but that the mechanisms of resistance vary across populations. Cestodes also evolved to counteract the defenses of their local hosts, eventually leading to specialization on a subset of hosts. We will use forward genetics to map the chromosomal loci associated with pathogen-driven host evolution, while crossing diverged cestode populations will uncover loci evolving due to host-driven selection. This work will be complemented with pharmacological and transgenic manipulations of candidate genes and molecular pathways, as well as forays into natural settings where we will use both experimental transplants and time-series data to understand how coevolution varies due to ecological and spatial constraints. Perhaps most exciting, there are several closely related stickleback species and cestode species that, despite millions of years of divergence, remain interfertile, and which enable us to characterize the genetics of coevolution across both micro- and macroevolutionary timescales.