Das bakteriell sezernierte Kombinom: Wirtsschädigung durch synergistisch-wirkende Exotoxine enterohämorrhagischer Escherichia coli

    Enterohämorrhagische Escherichia coli (EHEC) sezernieren einen Cocktail von Exotoxinen, die gemeinsam die intestinal-epitheliale und endotheliale Barriere schädigen und schwere Komplika-tionen wie das hämolytisch urämische Syndrom verursachen. Dieses Projekt zielt auf die Aufklärung des Wechselspiels von Virulenzfaktoren der EHEC-Serotypen O157:H- und O104:H4 und die Rolle, die Wirtsfaktoren bei diesem Prozess spielen, ab. Das Verständnis der Interaktionen der individuellen Determinanten kann zur Entwicklung vorbeugender Maßnahmen und spezifischer Therapien gegen EHEC-Infektionen beitragen.

    Forschungsgebiet: Infektionsbiologie, Pathogenese

    Prof. Dr. med. Alexander Mellmann   (07/2012 - 06/2024)
    Prof. Dr. rer. nat. Helge Karch              (07/2012 - 03/2019)

    Projektlaufzeit: Juli 2012 - Juni 2024

    • Publikationen

      Originalartikel

      • Faist A, Schloer S, Mecate-Zambrano A, Janowski J, Schreiber A, Boergeling Y, Conrad BCG, Kumar S, Toebben L, Schughart K, Baumgardt M, Kessler M, Hoenzke K, Hocke A, Trautmann M, Hartmann W, Kato H, Rescher U, Christersson A, Kuehn J, Mellmann A, Wolff T, Kuempers P, Rovas A, Wiewrodt R, Wiebe K, Barth P, Ludwig S, Brunotte L (2023) Inhibition of p38 signaling curtails the SARS-CoV-2 induced inflammatory response but retains the IFN-dependent antiviral defense of the lung epithelial barrier. Antiviral Res 209: 105475.  doi:10.1016/j.antiviral.2022.105475
      • Peng L, Dumevi RM, Chitto M, Haarmann N, Berger P, Koudelka G, Schmidt H, Mellmann A, Dobrindt U, Berger M (2022) A robust one-step recombineering system for enterohemorrhagic Escherichia coli. Microorganisms 10(9): 1689.  
        doi: 10.3390/microorganisms10091689.
      • Bielaszewska M, Daniel O, Nyč O, Mellmann A (2021) In vivo secretion of β-lactamase-carrying outer membrane vesicles as a mechanism of β-lactam therapy failure. Membranes (Basel) 11(11): 806.  doi: 10.3390/membranes11110806. 
      • Bielaszewska M, Greune L, Bauwens A, Dersch P, Mellmann A,  Rüter C (2021) Virulence Factor Cargo and Host Cell Interactions of Shiga Toxin-Producing Escherichia coli Outer Membrane Vesicles. Methods Mol Biol. 2291:177-205. doi:10.1007/978-1-0716-1339-9_8
      • Detzner J, Klein AL, Pohlentz G, Krojnewski E, Humpf HU, Mellmann A, Karch H, Müthing J (2021) Primary human renal proximal tubular epithelial cells (pHRPTEpiCs): Shiga toxin (Stx) glycosphingolipid receptors, Stx susceptibility, and interaction with membrane microdomains. Toxins (Basel) 13(8): 529.  doi: 10.3390/toxins13080529. 
      • Detzner J, Püttmann C, Pohlentz G, Humpf HU, Mellmann A, Karch H, Müthing J (2021) Primary Human Colon Epithelial Cells (pHCoEpiCs) Do Express the Shiga Toxin (Stx) Receptor Glycosphingolipids Gb3Cer and Gb4Cer and Are Largely Refractory but Not Resistant towards Stx. Int J Mol Sci 22(18): 10002.  doi: 10.3390/ijms221810002. 
      • Detzner J, Krojnewski E, Pohlentz G, Steil D, Humpf HU, Mellmann A, Karch H, Müthing J (2021) Shiga toxin (Stx)-binding glycosphingolipids of primary human renal cortical epithelial cells (pHRCEpiCs) and Stx-mediated cytotoxicity. Toxins (Basel) 13(2): 139.  doi: 10.3390/toxins13020139. 
      • Gati NS, Temme IJ, Middendorf-Bauchart B, Kehl A, Dobrindt U, Mellmann A (2021) Comparative phenotypic characterization of hybrid Shiga toxin-producing / uropathogenic Escherichia coli, canonical uropathogenic and Shiga toxin-producing Escherichia coli. Int J Med Microbiol 311(7): 151533.  doi: 10.1016/j.ijmm.2021.151533. 
      • Bielaszewska M, Daniel O, Karch H, Mellmann A (2020) Dissemination of the blaCTX-M-15 gene among Enterobacteriaceae via outer membrane vesicles. J Antimicrob Chemother 75(9): 2442-2451.  doi: 10.1093/jac/dkaa214.
      • Detzner J, Steil D, Pohlentz G, Legros N, Humpf HU, Mellmann A, Karch H, Müthing J (2020) Real-time interaction analysis of Shiga toxins and membrane microdomains of primary human brain microvascular endothelial cells. Glycobiology 30(3): 174-185.  doi: 10.1093/glycob/cwz091.
      • Kehl A, Kuhn R, Detzner J, Steil D, Müthing J, Karch H,Mellmann A (2020) Modeling native EHEC outer membrane vesicles by creating synthetic surrogates. Microorganisms 8(5): 673. doi: 10.3390/microorganisms8050673.
      • Kouzel IU, Kehl A, Berger P, Liashkovich I, Steil D, Makalowski W, Suzuki Y, Pohlentz G, Karch H, Mellmann A, Müthing J (2020) RAB5A and TRAPPC6B are novel targets for Shiga toxin 2a inactivation in kidney epithelial cells. Sci Rep 10(1): 4945.  doi: 10.1038/s41598-020-59694-w.
      • Berger, P., Kouzel, I.U., Berger, M., Haarmann, N., Dobrindt, U., Koudelka, G.B., and Mellmann, A. (2019) Carriage of Shiga toxin phage profoundly affects Escherichia coli gene expression and carbon source utilization. BMC Genomics 20, 504.
      • Bielaszewska, M., Marejkova, M., Bauwens, A., Kunsmann-Prokscha, L., Mellmann, A., and Karch, H. (2018) Enterohemorrhagic Escherichia coli O157 outer membrane vesicles induce interleukin 8 production in human intestinal epithelial cells by signaling via Toll-like receptors TLR4 and TLR5 and activation of the nuclear factor NF-?B. Int J Med Microbiol 308, 882-889.
      • Haarmann, N., Berger, M., Kouzel, I.U., Mellmann, A., and Berger, P. (2018) Comparative virulence characterization of the Shiga toxin phage-cured Escherichia coli O104:H4 and enteroaggregative Escherichia coli. Int J Med Microbiol 308, 912-920.
      • Kampmeier, S., Berger, M., Mellmann, A., Karch, H., and Berger, P. (2018) The 2011 German enterohemorrhagic Escherichia coli O104:H4 outbreak - The danger is still out there. Curr Top Microbiol Immunol 416, 117-148.
      • Steil, D., Pohlentz, G., Legros, N., Mormann, M., Mellmann, A., Karch, H., and Müthing, J. (2018) Combining mass spectrometry, surface acoustic wave interaction analysis, and cell viability assays for characterization of Shiga toxin subtypes of pathogenic Escherichia coli bacteria. Anal Chem 90, 8989-8997.
      • Bauwens A., Kunsmann L., Karch H., Mellmann A., Bielaszewska M. (2017) Antibiotic-mediated modulations of outer membrane vesicles in enterohemorrhagic Escherichia coli O104:H4 and O157:H7. Antimicrob Agents Chemother. 61(9):e00937-17. (doi: 10.1128/AAC.00937-17)
      • Bauwens A., Kunsmann L., Marejkova M., Zhang, W., Karch H., Bielaszewska M., et al. (2017) Intrahost milieu modulates production of outer membrane vesicles, vesicle-associated Shiga toxin 2a, and cytotoxicity in Escherichia coli O157:H7 and O104:H4. Environ Microbiol Rep. (doi:10.1111/1758-2229.12562.)
      • Bielaszewska M.*; Ruter, C.*; Bauwens, A.*; Greune, L.; Jarosch, K. A.; Steil, D.; Zhang, W.; He, X.; Lloubes, R.; Fruth, A.; Kim, K. S.; Schmidt, M. A.; Dobrindt, U.; Mellmann, A.; Karch, H. (2017) Host cell interactions of outer membrane vesicle-associated virulence factors of enterohemorrhagic Escherichia coli O157: Intracellular delivery, trafficking and mechanisms of cell injury. PLoS pathogens. 13(2):e1006159. (doi: 10.1371/journal.ppat.1006159)
      • Berger, P., Knodler, M., Forstner, K.U., Berger, M., Bertling, C., Sharma, C.M., Vogel, J., Karch, H., Dobrindt, U., and Mellmann, A (2016). The primary transcriptome of the Escherichia coli O104:H4 pAA plasmid and novel insights into its virulence gene expression and regulation. Sci Rep 6, 35307.
      • Kunsmann L, Rüter C, Bauwens A, Greune L, Glüder M, Kemper B, Fruth A, Wai SN, He X, Lloubes R, Schmidt MA, Dobrindt U, Mellmann A, Karch H, Bielaszewska M (2015) Virulence from vesicles: Novel mechanisms of host cell injury by Escherichia coli O104:H4 outbreak strain. Sci Rep 5: 13252.
      • Bielaszewska M, Schiller R, Lammer L, Bauwens A, Fruth A, Middendorf B, Schmidt MA, Tarr PI, Dobrindt U, Karch HMellmann A (2014) Heteropathogenic virulence and phylogeny reveal phased pathogenic metamorphosis in Escherichia coli O2:H6. EMBO Mol Med 6: 347-357. (IF 10,3)
      • Bielaszewska M, Rüter C, Kunsmann L, Greune L, Bauwens A, Zhang W, Kuczius T, Kim KS, Mellmann A, Schmidt MA, Karch H (2013) Enterohemorrhagic Escherichia coli hemolysin employs outer membrane vesicles to target mitochondria and cause endothelial and epithelial apoptosis. PLoS Pathog 9: e1003797. (IF 9,1)