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
Caenorhabditis elegans, the
spin-2 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
spin-2 and three additional genes in the
C. elegans 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
C. elegans immune response to bacterial pathogens. We found that mutations in the sphingosine kinase gene (
sphk-1) or in the S1P transporter genes
spin-2 or
spin-3 decreased nematode survival after infection with
Pseudomonas aeruginosa or
Enterococcus faecalis. In contrast to
spin-2 and
spin-3, mutating
spin-1 leads to an increase in resistance to
P. aeruginosa. Consistent with these results, when wild-type
C. elegans were supplemented with extracellular S1P, we found an increase in their lifespan when challenged with
P. aeruginosa and
E. faecalis. In comparison,
spin-2 and
spin-3 mutations suppressed the ability of S1P to rescue the worms from pathogen-mediated killing, whereas the
spin-1 mutation had no effect on the immune-enhancing activity of S1P. S1P demonstrated no antimicrobial activity toward
P. aeruginosa and
Escherichia coli and only minimal activity against
E. faecalis MMH594 (40 µM). These data suggest that
spin-2 and
spin-3, on the one hand, and
spin-1, on the other hand, transport S1P across cellular membranes in opposite directions. Finally, the immune modulatory effect of S1P was diminished in
C. eleganssek-1 and
pmk-1 mutants, suggesting that the immunomodulatory effects of S1P are mediated by the p38 MAPK signaling pathway.
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