Novel Immune Modulators Enhance Caenorhabditis elegans Resistance to Multiple Pathogens

Traditional treatments for bacterial infection have focused upon directly inhibiting growth of the pathogen. However, an equally important determinant of infection outcome is the host defense response. We previously performed a high-throughput chemical screen to identify small molecules that rescued the nematode Caenorhabditis elegans from infection by Pseudomonas aeruginosa. Over 20 of the hits stimulated host defense gene expression. During in-depth studies of five such molecules using microarray analysis, bioinformatic clustering, and RNAi knockdown of candidate gene targets, we identified PMK-1/p38 MAPK and SKN-1/Nrf2 as two key pathways modulated by these hits. Interestingly, the molecules studied did not depend on a single pathway for ameliorating P. aeruginosa pathogenesis in liquid-based assay, but did rely on the PMK-1/p38 MAPK pathway during a colonization-based infection assay on agar. A subset of these molecules was also protective against Enterococcus faecalis and Staphylococcus aureus. In general, the compounds showed little toxicity against mammalian cells or worms, consistent with their identification in a phenotypic, high-content screen. These molecules possess significant potential for use as tools to study innate immune processes There are 18 samples total that comprise three biological replicates of N2 young adult animals exposed to LK32, LK34, LK35, LK38, LK56, or DMSO control