Project Summary A priority in infectious disease research is to identify the genes that increase an individual’s resistance to a given infection. Variation in resistance clearly has a strong genetic basis, making it seemingly an ideal trait for identifying causal loci. Yet, genomic surveys have identified relatively few genes that consistently explain variation in disease outcomes in humans. A primary explanation for this gap is context-dependence: a gene may underlie parasite resistance at low but not high doses, or against one parasite strain but not others. This hypothesis argues that we cannot reliably detect the genes that matter for resistance without accounting for the genetic and environmental context in which hosts encounter their parasites. Ongoing projects associated with my parent award are addressing this need by characterizing genetic variation for parasite resistance across contexts using diverse host and parasite genotypes sampled from nature. Our powerful model system - the nematode Caenorhabditis elegans and its natural microsporidian parasites in the genus Nematocida – allows us to conduct highly controlled and replicated experiments across multiple contexts. We apply high-throughput phenotyping, experimental evolution, and experimental epidemiology to 1) characterize genetic variation in parasite resistance in natural populations, 2) evaluate the impact of parasite genotype on the expression of this genetic variation, and 3) examine the sensitivity of resistance genes to relevant environmental variables. Our efforts identified dose – the number of parasites a host encounters - as a major driver of the expression of genetic variation for resistance. We have designed key follow-up experiments to characterize the dose-dependency of resistance across host genotypes, and these experiments require precise estimates of parasite abundance within hosts and in their surrounding environment. Accordingly, I am requesting a supplement to this parent award to purchase a QIAcuity instrument for digital PCR to increase our precision, replication, and range of sample types for these experiments. This equipment will directly augment the impact of our projects on the scientific community and provide long-term support to my research program and department.