Advertisement

Role of Sphingolipids in Bacterial Infections

  • Katrin Anne Becker
  • Ryan Boudreau
  • Aaron Gardner
  • Aaron P. Seitz
  • Charles C. Caldwell
  • Xiang Li
  • Yang Zhang
  • Malcolm Brodlie
  • Michael J. Edwards
  • Erich Gulbins
Living reference work entry
Part of the Handbook of Hydrocarbon and Lipid Microbiology book series (HHLM)

Abstract

Lipids play a very important role in the infection of mammalian cells by different pathogens. Sphingolipids have been shown by numerous recent studies to possess a particularly essential role in infectious biology. Sphingolipids such as sphingomyelin, ceramide, and sphingosine organize cell membranes into distinct domains, called rafts that are enriched with sphingolipids and cholesterol. The generation of ceramide within the cell membrane results in the formation of large ceramide-enriched membrane platforms that serve the temporal and spatial organization of the cellular signaling machinery. Ceramide-enriched membrane platforms have critical functions for bacterial and viral infections. In addition, ceramide and sphingosine regulate the functions of enzymes, receptors, and organelles such as lysosomes, and therefore contribute to the control of the cellular response to pathogens. Finally, at least sphingosine has a direct antibacterial effect against many pathogens. Here, we present the diverse functions of sphingolipids in infectious biology and discuss mechanisms of their actions.

References

  1. Arikawa J, Ishibashi M, Kawashima M, Takagi Y, Ichikawa Y, Imokawa G (2002) Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus. J Invest Dermatol 119:433–439CrossRefPubMedGoogle Scholar
  2. Becker KA, Riethmüller J, Lüth A, Döring G, Kleuser B, Gulbins E (2010) Acid sphingomyelinase inhibitors normalize pulmonary ceramide and inflammation in cystic fibrosis. Am J Respir Cell Mol Biol 42:716–724CrossRefPubMedGoogle Scholar
  3. Becker KA, Henry B, Ziobro R, Tümmler B, Gulbins E, Grassmé H (2012) Role of CD95 in pulmonary inflammation and infection in cystic fibrosis. J Mol Med (Berl) 90:1011–1023CrossRefGoogle Scholar
  4. Becker KA, Fahsel B, Kemper H, Mayeres J, Li C, Wilker B, Keitsch S, Soddemann M, Sehl C, Kohnen M, Edwards MJ, Grassmé H, Caldwell CC, Seitz A, Fraunholz M, Gulbins E (2017a) Staphylococcus aureus alpha-toxin disrupts endothelial-cell tight junctions via acid sphingomyelinase and ceramide. Infect Immun 86. pii: e00606-17Google Scholar
  5. Becker KA, Li X, Seitz A, Steinmann J, Koch A, Schuchman E, Kamler M, Edwards MJ, Caldwell CC, Gulbins E (2017b) Neutrophils kill reactive oxygen species-resistant Pseudomonas aeruginosa by sphingosine. Cell Physiol Biochem 43:1603–1616CrossRefPubMedGoogle Scholar
  6. Bibel DJ, Aly R, Shinefield HR (1992) Antimicrobial activity of sphingosines. J Invest Dermatol 98:269–273CrossRefPubMedGoogle Scholar
  7. Bodas M, Min T, Mazur S, Vij N (2011) Critical modifier role of membrane-cystic fibrosis transmembrane conductance regulator-dependent ceramide signaling in lung injury and emphysema. J Immunol 186:602–613CrossRefPubMedGoogle Scholar
  8. Brodlie M, McKean MC, Johnson GE, Gray J, Fisher AJ, Corris PA, Lordan JL, Ward C (2010) Ceramide is increased in the lower airway epithelium of people with advanced cystic fibrosis lung disease. Am J Respir Crit Care Med 182:369–375CrossRefPubMedGoogle Scholar
  9. Brown DA, London E (1998) Functions of lipid rafts in biological membranes. Annu Rev Cell Dev Biol 14:111–136CrossRefPubMedGoogle Scholar
  10. Caretti A, Bragonzi A, Facchini M, De Fino I, Riva C, Gasco P, Musicanti C, Casas J, Fabriàs G, Ghidoni R, Signorelli P (2014) Anti-inflammatory action of lipid nanocarrier-delivered myriocin: therapeutic potential in cystic fibrosis. Biochim Biophys Acta 1840:586–594CrossRefPubMedGoogle Scholar
  11. Caretti A, Vasso M, Bonezzi FT, Gallina A, Trinchera M, Rossi A, Adami R, Casas J, Falleni M, Tosi D, Bragonzi A, Ghidoni R, Gelfi C, Signorelli P (2017) Myriocin treatment of CF lung infection and inflammation: complex analyses for enigmatic lipids. Naunyn Schmiedeberg’s Arch Pharmacol 390:775–790CrossRefGoogle Scholar
  12. CF foundation, patient registry annual report. (Bethesda, Maryland, U.S.A, 2010). http://www.cff.org/livingwithcf/carecenternetwork/patientregistry/
  13. Dobrowsky RT, Hannun YA (1993) Ceramide-activated protein phosphatase: partial purification and relationship to protein phosphatase 2A. Adv Lipid Res 25:91–104PubMedGoogle Scholar
  14. Elborn JS (2016) Cystic fibrosis. Lancet 5:681–683Google Scholar
  15. Esen M, Schreiner B, Jendrossek V, Lang F, Fassbender K, Grassmé H, Gulbins E (2001) Mechanisms of Staphylococcus aureus induced apoptosis of human endothelial cells. Apoptosis 6:431–439CrossRefPubMedGoogle Scholar
  16. Fischer CL, Walters KS, Drake DR, Blanchette DR, Dawson DV, Brogden KA, Wertz PW (2013) Sphingoid bases are taken up by Escherichia coli and Staphylococcus aureus and induce ultrastructural damage. Skin Pharmacol Physiol 26:36–44CrossRefPubMedGoogle Scholar
  17. Gluschko A, Herb M, Wiegmann K, Krut O, Neiss WF, Utermöhlen O, Krönke M, Schramm M (2018) The β2 Integrin Mac-1 induces protective LC3-associated phagocytosis of Listeria monocytogenes. Cell Host Microbe 23:324–337CrossRefPubMedGoogle Scholar
  18. Grassmé H, Gulbins E, Brenner B, Ferlinz K, Sandhoff K, Harzer K, Lang F, Meyer TF (1997) Acidic sphingomyelinase mediates entry of N. gonorrhoeae into nonphagocytic cells. Cell 91:605–615CrossRefPubMedGoogle Scholar
  19. Grassmé H, Kirschnek S, Riethmueller J, Riehle A, von Kürthy G, Lang F, Weller M, Gulbins E (2000) Host defense to Pseudomonas aeruginosa requires CD95/CD95 ligand interaction on epithelial cells. Science 290:527–530CrossRefPubMedGoogle Scholar
  20. Grassmé H, Jekle A, Riehle A, Schwarz H, Berger J, Sandhoff K (2001) CD95 signaling via ceramide-rich membrane rafts. J Biol Chem 276:20589–20596CrossRefPubMedGoogle Scholar
  21. Grassmé H, Jendrossek V, Riehle A, von Kurthy G, Berger J, Schwarz H, Weller M, Kolesnick R, Gulbins E (2003) Host defense against Pseudomonas aeruginosa requires ceramide-rich membrane rafts. Nat Med 9:322–330CrossRefPubMedGoogle Scholar
  22. Grassmé H, Henry B, Ziobro R, Becker KA, Riethmüller J, Gardner A, Seitz AP, Steinmann J, Lang S, Ward C, Schuchman EH, Caldwell CC, Kamler M, Edwards MJ, Brodlie M, Gulbins E (2017) β1-Integrin accumulates in cystic fibrosis luminal airway epithelial membranes and decreases sphingosine, promoting bacterial infections. Cell Host Microbe 21:707–718CrossRefPubMedPubMedCentralGoogle Scholar
  23. Gulbins E, Szabo I, Baltzer K, Lang F (1997) Ceramide-induced inhibition of T lymphocyte voltage-gated potassium channel is mediated by tyrosine kinases. Proc Natl Acad Sci U S A 94:7661–7666CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9:139–150CrossRefPubMedGoogle Scholar
  25. Hauck CR, Grassmé H, Bock J, Jendrossek V, Ferlinz K, Meyer TF, Gulbins E (2000) Acid sphingomyelinase is involved in CEACAM receptor-mediated phagocytosis of Neisseria gonorrhoeae. FEBS Lett 478:260–266CrossRefPubMedGoogle Scholar
  26. Heinrich M, Wickel M, Schneider-Brachert W, Sandberg C, Gahr J, Schwandner R (1999) Cathepsin D targeted by acid sphingomyelinase-derived ceramide. EMBO J 18:5252–5263CrossRefPubMedPubMedCentralGoogle Scholar
  27. Henry BD, Neill DR, Becker KA, Gore S, Bricio-Moreno L, Ziobro R, Edwards MJ, Mühlemann K, Steinmann J, Kleuser B, Japtok L, Luginbühl M, Wolfmeier SA, Gulbins E, Kadioglu A, Draeger A, Babiychuk EB (2015) Biomimetic, toxin-sequestrating therapy for the treatment of severe invasive bacterial infections. Nat Biotechnol 33:81–88CrossRefPubMedGoogle Scholar
  28. Huwiler A, Johansen B, Skarstad A, Pfeilschifter J (2001) Ceramide binds to the CaLB domain of cytosolic phospholipase A2 and facilitates its membrane docking and arachidonic acid release. FASEB J 15:7–9CrossRefPubMedGoogle Scholar
  29. Ishibashi Y, Nakasone T, Kiyohara M, Horibata Y, Sakaguchi K, Hijikata A, Ichinose S, Omori A, Yasui Y, Ishida H, Kiso M, Okino N, Ito M (2007) A novel endoglycocera-midase hydrolyzes oligogalactosylceramides to produce galactooligosaccharides and ceramides. J Biol Chem 282:11386–11396CrossRefPubMedGoogle Scholar
  30. Itokazu Y, Pagano RE, Schroeder AS, O'Grady SM, Limper AH, Marks DL (2014) Reduced GM1 ganglioside in CFTR-deficient human airway cells results in decreased β1-integrin signaling and delayed wound repair. Am J Physiol Cell Physiol 306:C819–C830CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kannan S, Audet A, Huang H, Chen LJ, Wu M (2008) Cholesterol-rich membrane rafts and Lyn are involved in phagocytosis during Pseudomonas aeruginosa infection. Infect Immun 180:2396–2408Google Scholar
  32. Keitsch S, Riethmüller J, Soddemann M, Sehl C, Wilker B, Edwards MJ, Caldwell CC, Fraunholz M, Gulbins E, Becker KA (2018) Pulmonary infection of cystic fibrosis mice with Staphylococcus aureus requires expression of α-toxin. Biol Chem 399:1203.  https://doi.org/10.1515/hsz-2018-0161. pii: /j/bchm.ahead-of-print/hsz-2018-0161/hsz-2018-0161.xmlCrossRefPubMedGoogle Scholar
  33. Kolesnick RN, Goni FM, Alonso A (2000) Compartmentalization of ceramide signaling: physical foundations and biological effects. J Cell Physiol 184:285–300CrossRefPubMedGoogle Scholar
  34. Kovacic B, Sehl C, Wilker B, Kamler M, Gulbins E, Becker KA (2017) Glucosylceramide critically contributes to the host defense of cystic fibrosis lungs. Cell Physiol Biochem 41:1208–1218CrossRefGoogle Scholar
  35. Kowalski MP, Pier GB (2004) Localization of cystic fibrosis transmembrane conductance regulator to lipid rafts of epithelial cells is required for Pseudomonas aeruginosa-induced cellular activation. J Immunol 172:418–425CrossRefGoogle Scholar
  36. Kowalski MP, Dubouix-Bourandy A, Bajmoczi M, Golan DE, Zaidi T, Coutinho-Sledge YS, Gygi MP, Gygi SP, Wiemer EAC, Pier GB (2007) Host resistance to lung infection mediated by major vault protein in epithelial cells. Science 317:130–132CrossRefPubMedPubMedCentralGoogle Scholar
  37. Lepple-Wienhues A, Belka C, Laun T, Jekle A, Walter B, Wieland U (1999) Stimulation of CD95 (Fas) blocks T lymphocyte calcium channels through sphingomyelinase and sphingolipids. Proc Natl Acad Sci U S A 96:13795–13800CrossRefPubMedPubMedCentralGoogle Scholar
  38. Li C, Peng H, Japtok L, Seitz A, Riehle A, Wilker B, Soddemann M, Kleuser B, Edwards M, Lammas D, Zhang Y, Gulbins E, Grassmé H (2016) Inhibition of neutral sphingomyelinase protects mice against systemic tuberculosis. Front Biosci 8:311–325CrossRefGoogle Scholar
  39. Li C, Wu Y, Orian-Rousseau V, Zhang Y, Gulbins E, Grassme H (2017) Regulation of Staphylococcus aureus infection of macrophages by CD44, reactive oxygen species and acid sphingomyelinase. Antioxid Redox Signal.  https://doi.org/10.1089/ars.2017.6994
  40. Ma J, Gulbins E, Edwards MJ, Caldwell CC, Fraunholz M, Becker KA (2017) Staphylococcus aureus α-Toxin induces inflammatory cytokines via lysosomal acid sphingomyelinase and ceramides. Cell Physiol Biochem 43:2170–2184CrossRefPubMedGoogle Scholar
  41. Muller G, Ayoub M, Storz P, Rennecke J, Fabbro D, Pfizenmaier K (1995) PKC zeta is a molecular switch in signal transduction of TNF-alpha, bifunctionally regulated by ceramide and arachidonic acid. EMBO J 14:1961–1969CrossRefPubMedPubMedCentralGoogle Scholar
  42. Nurminen TA, Holopainen JM, Zhao H, Kinnunen PK (2002) Observation of topical catalysis by sphingomyelinase coupled to microspheres. J Am Chem Soc 124:12129–12134CrossRefPubMedGoogle Scholar
  43. Okino N, He X, Gatt S, Sandhoff K, Ito M, Schuchman EH (2003) The reverse activity of human acid ceramidase. J Biol Chem 278:29948–29953CrossRefPubMedGoogle Scholar
  44. Peng H, Li C, Kadow S, Henry BD, Steinmann J, Becker KA, Riehle A, Beckmann N, Wilker B, Li PL, Pritts T, Edwards MJ, Zhang Y, Gulbins E, Grassmé H (2015) Acid sphingomyelinase inhibition protects mice from lung edema and lethal Staphylococcus aureus sepsis. J Mol Med (Berl) 93:675–689CrossRefGoogle Scholar
  45. Pewzner-Jung Y, Tavakoli Tabazavareh S, Grassmé H, Becker KA, Japtok L, Steinmann J, Joseph T, Lang S, Tuemmler B, Schuchman EH, Lentsch AB, Kleuser B, Edwards MJ, Futerman AH, Gulbins E (2014) Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa. EMBO Mol Med 6:1205–1211CrossRefPubMedPubMedCentralGoogle Scholar
  46. Pier GB, Grout M, Zaidi TS, Olsen JC, Johnson LG, Yankaskas JR, Goldberg JB (1996) Role of mutant CFTR in hypersusceptibility of cystic fibrosis patients to lung infections. Science 271:64–67CrossRefPubMedPubMedCentralGoogle Scholar
  47. Quinn RA, Lim YW, Mak TD, Whiteson K, Furlan M, Conrad D, Rohwer F, Dorrestein P (2016) Metabolomics of pulmonary exacerbations reveals the personalized nature of cystic fibrosis disease. PeerJ 4:e2174CrossRefPubMedPubMedCentralGoogle Scholar
  48. Ratjen F, Döring G (2003) Cystic fibrosis. Lancet 361:681–689CrossRefPubMedGoogle Scholar
  49. Rice TC, Pugh AM, Seitz AP, Gulbins E, Nomellini V, Caldwell CC (2017) Sphingosine rescues aged mice from pulmonary pseudomonas infection. J Surg Res 219:354–359CrossRefPubMedPubMedCentralGoogle Scholar
  50. Roca FJ, Ramakrishnan L (2013) TNF dually mediates resistance and susceptibility to Mycobacteria via mitochondrial reactive oxygen species. Cell 153:1–14CrossRefGoogle Scholar
  51. Saiman L, Prince A (1993) Pseudomonas aeruginosa pili bind to asialoGM1, which is increased on the surface of cystic fibrosis epithelial cells. J Clin Invest 92:1875–1880CrossRefPubMedPubMedCentralGoogle Scholar
  52. Schramm M, Herz J, Haas A, Krönke M, Utermöhlen O (2008) Acid spingomyelinase is required for efficient phago-lysosomal fusion. Cell Microbiol 10:1839–1853CrossRefPubMedGoogle Scholar
  53. Simonis A, Hebling S, Gulbins E, Schneider-Schaulies S, Schubert-Unkmeir A (2014) Differential activation of acid sphingomyelinase and ceramide release determines invasiveness of Neisseria meningitidis into brain endothelial cells. PLoS Pathog 10:e1004160CrossRefPubMedPubMedCentralGoogle Scholar
  54. Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387:569–572CrossRefGoogle Scholar
  55. Singer SJ, Nicolson GL (1972) The fluid mosaic model of the structure of cell membranes. Science 175:720–731CrossRefPubMedGoogle Scholar
  56. Szabo I, Gulbins E, Apfel H, Zhang X, Barth P, Busch AE (1996) Tyrosine phosphorylation-dependent suppression of a voltage-gated K+ channel in T lymphocytes upon Fas stimulation. J Biol Chem 271:20465–20469CrossRefPubMedGoogle Scholar
  57. Tavakoli Tabazavareh S, Seitz A, Jernigan P, Sehl C, Keitsch S, Lang S, Kahl BC, Edwards M, Grassmé H, Gulbins E, Becker KA (2016) Lack of sphingosine causes susceptibility to pulmonary Staphylococcus aureus infections in cystic fibrosis. Cell Physiol Biochem 38:2094–2102CrossRefPubMedGoogle Scholar
  58. Teichgräber V, Ulrich M, Endlich N, Riethmüller J, Wilker B, De Oliveira-Munding CC, van Heeckeren AM, Barr ML, von Kürthy G, Schmid KW, Weller M, Tümmler B, Lang F, Grassmé H, Döring G, Gulbins E (2008) Ceramide accumulation mediates inflammation, cell death and infection susceptibility in cystic fibrosis. Nat Med 14:382–391CrossRefPubMedGoogle Scholar
  59. Ulrich M, Worlitzsch D, Viglio S, Siegmann N, Iadarola P, Shute JK, Geiser M, Pier GB, Friedel G, Barr ML, Schuster A, Meyer KC, Ratjen F, Bjarnsholt T, Gulbins E, Döring G (2010) Alveolar inflammation in cystic fibrosis. J Cyst Fibros 9:217–227CrossRefPubMedPubMedCentralGoogle Scholar
  60. Utermöhlen O, Karow U, Lohler J, Krönke M (2003) Severe impairment in early host defense against Listeria monocytogenes in mice deficient in acid sphingomyelinase. J Immunol 170:2621–2628CrossRefPubMedGoogle Scholar
  61. Xu X, Bittman R, Duportail G, Heissler D, Vilcheze C, London E (2001) Effect of the structure of natural sterols and sphingolipids on the formation of ordered sphingolipid/sterol domains (rafts). Comparison of cholesterol to plant, fungal, and disease-associated sterols and comparison of sphingomyelin, cerebrosides, and ceramide. J Biol Chem 276:33540–33546CrossRefPubMedGoogle Scholar
  62. Yamamoto N, Yamamoto N, Petroll MW, Cavanagh HD, Jester JV (2005) Internalization of Pseudomonas aeruginosa is mediated by lipid rafts in contact lens-wearing rabbit and cultured human corneal epithelial cells. Invest Ophthalmol Vis Sci 46:1348–1355CrossRefPubMedGoogle Scholar
  63. Yao B, Zhang Y, Delikat S, Mathias S, Basu S, Kolesnick R (1995) Phosphorylation of Raf by ceramide-activated protein kinase. Nature 378:307–310CrossRefPubMedGoogle Scholar
  64. Zhang Y, Li X, Carpinteiro A, Gulbins E (2008) Acid sphingomyelinase amplifies redox signaling in Pseudomonas aeruginosa-induced macrophage apoptosis. J Immunol 181:4247–4254CrossRefPubMedGoogle Scholar
  65. Zhang Y, Li X, Grassmé H, Döring G, Gulbins E (2009) Alterations in ceramide concentration and pH determine the release of reactive oxygen species by Cftr-deficient macrophages on infection. J Immunol 184:5104–5111CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Katrin Anne Becker
    • 1
  • Ryan Boudreau
    • 2
  • Aaron Gardner
    • 3
  • Aaron P. Seitz
    • 2
  • Charles C. Caldwell
    • 2
  • Xiang Li
    • 4
  • Yang Zhang
    • 4
  • Malcolm Brodlie
    • 3
  • Michael J. Edwards
    • 2
  • Erich Gulbins
    • 1
    • 2
  1. 1.Department of Molecular BiologyUniversity Hospital Essen, University of Duisburg-EssenEssenGermany
  2. 2.Department of SurgeryUniversity of CincinnatiCincinnatiUSA
  3. 3.Institute of Cellular MedicineNewcastle UniversityNewcastle upon TyneUK
  4. 4.Department of Pharmacological & Pharmaceutical SciencesCollege of Pharmacy University of HoustonHoustonUSA

Personalised recommendations