In the Model Host Caenorhabditis elegans , Sphingosine-1-Phosphate-Mediated Signaling Increases Immunity toward Human Opportunistic Bacteria

Sphingosine-1-phophate (S1P) is a sphingolipid-derived signaling molecule that controls diverse cellular functions including cell growth, homeostasis, and stress responses. In a variety of metazoans, cytosolic S1P is transported into the extracellular space where it activates S1P receptors in a concentration-dependent manner. In the free-living nematode , the gene, which encodes a S1P transporter, is activated during Gram-positive or Gram-negative bacterial infection of the intestine. However, the role during infection of and three additional genes in the genome encoding other putative S1P transporters has not been elucidated. Here, we report an evolutionally conserved function for S1P and a non-canonical role for S1P transporters in the immune response to bacterial pathogens. We found that mutations in the sphingosine kinase gene ( ) or in the S1P transporter genes or decreased nematode survival after infection with or . In contrast to and , mutating leads to an increase in resistance to . Consistent with these results, when wild-type were supplemented with extracellular S1P, we found an increase in their lifespan when challenged with and . In comparison, and mutations suppressed the ability of S1P to rescue the worms from pathogen-mediated killing, whereas the mutation had no effect on the immune-enhancing activity of S1P. S1P demonstrated no antimicrobial activity toward and and only minimal activity against MMH594 (40 µM). These data suggest that and , on the one hand, and , on the other hand, transport S1P across cellular membranes in opposite directions. Finally, the immune modulatory effect of S1P was diminished in and mutants, suggesting that the immunomodulatory effects of S1P are mediated by the p38 MAPK signaling pathway.