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Deutsch Intern
    Institut für Hygiene und Mikrobiologie

    Sphingolipids and meningococcal meningitis

     

    Sphingolipid-enriched membrane microdomains contribute to a variety of cellular processes, including signal transduction and vesicle trafficking. Interestingly, a number of pathogens exploit the endocytic properties of Sphingolipid-enriched membrane microdomains to enter into host cells. In particular, N. meningitidis modulates sphingolipid levels on brain endothelial cells and uses ceramide-rich membrane platforms as a port of entry into non-phagocytic cells (Simonis et al, PLoS Pathog. 2014 Jun 12;10(6):e1004160). We found that both live, piliated N. meningitidis and pilus-enriched fractions trigger transient ASM surface display of the enzyme acid sphingomyelinase, followed by the formation of ceramide-rich platforms (Peters et al, Infect Immun. 2019 Jun 3. pii: IAI.00410-19).

    Ceramides can further be metabolized to sphingosine-1-phosphate (S1P), a sphingolipid metabolite that has both cell-intrinsic and cell-extrinsic activity, affecting cell homeostasis and function. Within the newly funded GRK2581 we seek to analyse the role of the cell-extrinsic function of S1P, where it acts as a ligand for a family of five G-protein coupled receptors, known as S1P receptors (S1P1-5) and aim to characterize the role of S1P and S1P1-2 during the inflammatory response and the modulation of barrier permeability and integrity during the pathophysiology of meningococcal

    This project currently receives funding from DFG and is part of the Forschergruppe FOR2123

    Funding - 2017-2020

    FOR 2123 Sphingolipid dynamics in infection control

    Untersuchung zur funktionellen Relevanz von Sphingomyelinasen und Ceramiden in der Pathogenese der Meningokokkeninfektion“ (SCHU 2394/2-2; Teilprojekt P03).

    We currently work in close collaboration with Prof. Markus Sauer, Prof. Cristian Stigloher and Prof. Jürgen Seibel.

    Funding - 2014-2016

    FOR 2123 Sphingolipid dynamics in infection control

    Untersuchung zur funktionellen Relevanz von Sphingomyelinasen und Ceramiden in der Pathogenese der Meningokokkeninfektion“ (SCHU 2394/2-1; Teilprojekt P03)

    References

    Schlegel J, Peters S, Doose S, Schubert-Unkmeir A, Sauer M (2019) Super-resolution microscopy reveals local accumulation of plasma membrane gangliosides at Neisseria meningitidis invasion sites. Front Cell Dev Biol. 2019 Sept 7, 194.

    Peters S, Schlegel J, Becam J, Avota E, Sauer M, Schubert-Unkmeir A. Neisseria meningitidis type IV pili trigger Ca2+-dependent lysosomal trafficking of the acid sphingomyelinase to enhance surface ceramide levels. Infect Immun. 2019 Jun 3. pii: IAI.00410-19. doi: 10.1128/IAI.00410-19.

    Simonis A, Schubert-Unkmeir A. The role of acid sphingomyelinase and modulation of sphingolipid metabolism in bacterial infection. Biol Chem. 2018 Sep 25;399(10):1135-1146.

    Becam J, Walter T, Burgert A, Schlegel J, Sauer M, Seibel J, Schubert-Unkmeir A. Antibacterial activity of ceramide and ceramide analogs against pathogenic Neisseria. Sci Rep. 2017 Dec 15;7(1):17627.

    Burgert A, Schlegel J, Bécam J, Doose S, Bieberich E, Schubert-Unkmeir A, Sauer M.Characterization of Plasma Membrane Ceramides by Super-Resolution Microscopy. Angew Chem Int Ed Engl. 2017 Apr 5. doi: 10.1002/anie.201700570.

    Walter T, Collenburg L, Japtok L, Kleuser B, Schneider-Schaulies S, Müller N, Becam J, Schubert-Unkmeir A, Kong JN, Bieberich E, Seibel J. Incorporation and visualization of azido-functionalized N-oleoyl serinol in Jurkat cells, mouse brain astrocytes, 3T3 fibroblasts and human brain microvascular endothelial cells. Chem Commun (Camb). 2016 Jun 30;52(55):8612-4.

    Simonis, A., Hebling, S., Gulbins, E., Schneider-Schaulies, S. and Schubert-Unkmeir, A. Differential activation of acid sphingomyelinase and ceramide release determines invasiveness of Neisseria meningitidis into brain endothelial cells. PLoS Pathog. 2014 Jun 12;10(6):e1004160.