The role of the Daf-2 insulin-like signaling pathway in Caenorhabditis elegans innate immunity

The C. elegans DAF-2/DAF-16 insulin-like signaling pathway, which regulates lifespan and stress resistance, has also been implicated in resistance to bacterial pathogens. The mechanism by which insulin-like signaling regulates pathogen resistance and the role of insulin-like signaling in regulating responses to pathogens is largely unknown. The co-regulation of lifespan and pathogen resistance raises the possibility that the increased longevity and the pathogen resistance of insulin-like signaling pathway mutants are reflections of the same underlying mechanism. I found that regulation of lifespan and resistance to the bacterial pathogen Pseudomonas aeruginosa is mediated by both shared and genetically distinguishable mechanisms. Resistance is associated with DAF-16 activity, with the ability to clear infection, and with antimicrobial gene expression. However, a variety of genetic manipulations that extend lifespan have no effect on pathogen resistance. I also found that during P. aeruginosa infection, the expression of a subset of immune defense genes is suppressed by activating the insulin-like signaling pathway. In particular, the downstream transcription factor DAF-16 is suppressed by P. aeruginosa infection, an effect mediated by the insulin-like peptide INS-7, and requiring the P. aeruginosa virulence regulators GacA, LasR and RhlR. Overall, I establish that aging and innate immunity are regulated by genetically distinct mechanisms and that P. aeruginosa suppresses host immune defense through its effects on insulin-like signaling.