Inappropriate activation of innate immune responses in nematode intestinal epithelial cells underlies the pathophysiology of some inflammatory disorders. Immunostimulatory xenobiotics are known to protect nematodes from bacterial infection (e.g., Pseudomonas aeruginosa). Conversely, these same xenobiotics are toxic to uninfected nematodes. These xenobiotics were subjected to a forward genetic screen in uninfected nematodes to identify nematode mutants that were resistant to the deleterious effects of these xenobiotics. These resistant nematode strains contained hypomorphic mutations in each of the known components of the p38 MAP kinase cassette (tir-1, nsy-1, sek-1 and pmk-1), demonstrating that hyperstimulation of p38 MAPK innate immune responses may be responsible for the induced toxicity. A second genetic screen using dominant activators of the p38 MAPK pathway identified a single allele that had a gain-of-function (gf) mutation in nsy-1, the MAP kinase kinase kinase that acts upstream of p38 MAPK pmk-1.
