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Open AccessArticle

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

1
Division of Infectious Diseases, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA
2
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea
3
Department of Genetics, Harvard Medical School and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(21), 7813; https://doi.org/10.3390/ijms21217813
Received: 26 August 2020 / Revised: 18 October 2020 / Accepted: 20 October 2020 / Published: 22 October 2020
(This article belongs to the Special Issue Molecular Mechanisms of Host-Pathogen Interaction)
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. View Full-Text
Keywords: Keywords: Sphingosine-1-phosphate; S1P; S1P kinase; S1P transporters; pathogenic bacteria; immunity; Caenorhabditis elegans Keywords: Sphingosine-1-phosphate; S1P; S1P kinase; S1P transporters; pathogenic bacteria; immunity; Caenorhabditis elegans
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MDPI and ACS Style

Lee, K.; Escobar, I.; Jang, Y.; Kim, W.; Ausubel, F.M.; Mylonakis, E. In the Model Host Caenorhabditis elegans, Sphingosine-1-Phosphate-Mediated Signaling Increases Immunity toward Human Opportunistic Bacteria. Int. J. Mol. Sci. 2020, 21, 7813.

AMA Style

Lee K, Escobar I, Jang Y, Kim W, Ausubel FM, Mylonakis E. In the Model Host Caenorhabditis elegans, Sphingosine-1-Phosphate-Mediated Signaling Increases Immunity toward Human Opportunistic Bacteria. International Journal of Molecular Sciences. 2020; 21(21):7813.

Chicago/Turabian Style

Lee, Kiho; Escobar, Iliana; Jang, Yeeun; Kim, Wooseong; Ausubel, Frederick M.; Mylonakis, Eleftherios. 2020. "In the Model Host Caenorhabditis elegans, Sphingosine-1-Phosphate-Mediated Signaling Increases Immunity toward Human Opportunistic Bacteria" Int. J. Mol. Sci. 21, no. 21: 7813.

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