The nematode Caenorhabditis elegans responds to pathogenic bacteria with conserved innate immune responses and pathogen avoidance behaviors. We investigated natural variation in C. elegans responses to different pathogen infections, using a collection of advanced intercross recombinant inbred lines (RILs) between the laboratory wild-type strain N2 and a wild isolate from Hawaii CB4856. Initially, we chose to focus on the opportunistic human pathogen Pseudomonas aeruginosa, a gram-negative, aerobic bacterium. Quantitative trait mapping of the susceptibilities of 126 RILs led to the identification of a polymorphism in the
npr-1 gene as causal in the difference in susceptibility to P. aeruginosa between these two strains. We showed that the mechanism of NPR-1-mediated pathogen resistance is through oxygen-dependent behavioral avoidance rather than through direct regulation of innate immunity. Because the
npr-1 allele present in the N2 strain is a lab-derived gain-of-function allele (1), we sought natural variants involved in pathogen resistance by scoring susceptibility to P. aeruginosa in only those RILs with the ancestral
npr-1 allele (found in CB4856). Through quantitative genetic analysis of 89 additional strains, we identified a second quantitative trait locus (QTL) on LGV. We will discuss our progress in determining the gene underlying this novel QTL. Subsequently, we investigated differences in the susceptibilities of N2 and CB4856 to Bacillus thuringiensis, Candida albicans, Cryptococcus neoformans, Enterococcus faecalis, Serratia marcescens, and Staphylococcus aureus. Assays using the gram-positive bacterium S. aureus had the most robust survival difference between the two parental strains. Quantitative trait mapping of the susceptibilities of 73 RILs led to a causal polymorphism in the
npr-1 gene, indicating that behavior determines the susceptibility to this pathogen as well. We will present our progress on the identification of additional QTL controlling susceptibility to S. aureus. (1) McGrath PT et al. Neuron 2009; 61(5):692-699.