GRK 1409: Molekulare Interaktionen von Pathogenen mit biotischen und abiotischen Oberflächen
Zusammenfassung der Projektergebnisse
Das Graduiertenkolleg hat über die gesamte Förderperiode sein erfolgreiches Programm durchgeführt und fortgesetzt und in einem interdisziplinären, thematisch fokussierten Ansatz die molekularen Interaktionen von pathogenen Mikroorganismen mit biotischen und abiotischen Oberflächen analysiert und charakterisiert. Wechselwirkungen mikrobieller Erreger (Bakterien, Viren, Pilzen, Parasiten) mit Epithel- und Endothelzellbarrieren sowie den Immunzellen des Wirts und die durch diese Interaktionen ausgelösten Signale spielen im Infektionsgeschehen eine entscheidende Rolle. Trotz zahlreicher gemeinsamer oder zumindest strategisch verwandter grundlegender Mechanismen ist der Erkenntnisgewinn der Bakteriologie, Mykologie, Parasitologie und Virologie bisher eher auf getrennten Wegen und häufig durch parallele Forschungsanstrengungen erzielt worden. Dieses Graduiertenkolleg hat daher ganz bewusst die Grenzen bisheriger Disziplinen überschritten und am Beispiel verschiedener Modellsysteme in einem interdisziplinären und breit gefächerten Ansatz diese komplexe Forschungsthematik bearbeitet. Die in der zweiten Förderperiode erfolgte Erweiterung der Fakultät des GRK1409 und damit auch der untersuchten Modellsysteme hat dazu beigetragen, den Horizont unserer Graduierten zu erweitern. Insgesamt beteiligten sich 23 Wissenschaftlerinnen und Wissenschaftler am GRK1409. Dadurch konnten wir die notwendige Expertise aus mehreren Fachrichtungen vereinen und bündeln. Ziel des Graduiertenkollegs war es, die Komplexität dieser Vorgänge sowohl auf der Seite der Mikroorganismen als auch auf der Seite der Wirtszellen besser zu verstehen und die beteiligten Doktoranden in einem integrativen systemübergreifenden Ansatz wissenschaftlich zu fördern und auszubilden. Die Graduierten (Mitglieder und assoziierte Mitglieder gleichermaßen) wurden im GRK durch ein interdisziplinäres Programm in moderner, d. h. interdisziplinär ausgerichteter, molekularer Infektionsbiologie unterrichtet und weitergebildet. Neben der wissenschaftlichen Qualifizierung setzte das Programm durch ein erweitertes Angebot an ’soft-skills training courses’ einen zusätzlichen Akzent in ’career development and mentoring’. Das GRK ermutigte und unterstützte die Teilnahme der Graduierten an nationalen und internationalen Tagungen. Zusätzlich wurden zahlreiche passgenaue internationale Forschungsaufenthalte im Rahmen des ’International Laboratory Exchange Programs’ in exzellenten Laboratorien weltweit ermöglicht. Diese Fördermaßnahmen intensivierten besonders den Kontakt zu auswärtigen Forschungsgruppen und trugen dadurch zur Integration der Mitglieder des GRK in internationale Forschungsnetzwerke bei. Wir sind überzeugt, im Rahmen des GRK 1409 durch die aufeinander abgestimmten Förder- und Qualifizierungsmaßnahmen international konkurrenzfähige junge Wissenschaftlerinnen und Wissenschaftler deutlich gefördert und weitergebildet zu haben.
Projektbezogene Publikationen (Auswahl)
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(2007) Characterization of bacteria-binding glycosphingolipids by mass spectrometry. Int. J. Med., Microbiol., 297S1, 43, 57
Müsken, A., Zhang, W., Souady, J., Dreisewerd, K., Bielaszewska, M., Friedrich, A.W., Peter-Katalini, J., Karch, H., and Müthing, J.
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(2008) Anaerobic conditions promote expression of Sfp fimbriae and adherence of sorbitol-fermenting enterohemorrhagic Escherichia coli O157:NM to human intestinal epithelial cells. Appl. Environ. Microbiol., 74:1087-1093
Müsken, A., Bielaszewska, M., Greune, L., Schweppe, C. H., Müthing, J., Schmidt, H., Schmidt, M. A., Karch, H., and Zhang, W.
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(2008) Apoptosis leads to a degradation of vital components of active nuclear transport and a dissociation of the nuclear lamina. Proc. Natl. Acad. Sci. USA, 105(32):11236-41
Kramer, A., Liashkovich, I., Oberleithner, H., Ludwig, S., Mazur, I., and Shahin, V.
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(2008) Atomic force microscopy visualises a hydrophobic meshwork in the central channel of the nuclear pore. Pflügers Arch., 456(1):155-62
Kramer, A., Liashkovich, I., Ludwig, Y., and Shahin, V.
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(2008) Exceptional mechanical and structural stability of HSV-1 unveiled with fluid atomic force microscopy. J. Cell. Sci., 121(Pt 14):2287-92
Liashkovich, I., Hafezi, W., Kühn, J. E., Oberleithner, H., Kramer, A., and Shahin, V.
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(2008) Function of MAP-Kinase activated protein kinases in influenza A virus infection - linking MAPK signaling to PKR inhibition. Cytokine, 43(3):237
Luig, C., and Ludwig, S.
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(2008) Human leukocyte-derived cell lines differ in their expression of Shiga toxin receptors. Int. J. Med. Microbiol., 298S2: 45, 74
Hoffmann, P., Hülsewig, M., Duvar, S., Ziehr, H., Dreisewerd, K., Peter-Katalini, J.,Schmidt, M. A. , Karch, H., and Müthing, J.
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(2009) AFM imaging of functionalized carbon nanotubes on biological membranes. Nanotechnology, 20(43): 434001
Lamprecht, C., Liashkovich, I., Neves, V., Danzberger, J., Heister, E., Rangl, M., Coley, H. M., McFadden, J., Flahaut, E., Gruber, H. J., Hinterdorfer, P., Kienberger, F., and Ebner, A.
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(2009) Bacterial motility and clustering guided by microcontact printing. Nano Lett., 9(12): 4553-4557
Holz, C., Opitz, D., Mehlich, J., Ravoo, B. J., and Maier, B.
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(2009) Biosynthesis of the red pigment bikaverin in Fusarium fujikuroi: genes, their function and regulation. Mol. Microbiol., 72: 931–946
Wiemann, P., Willmann, A., Straeten, M., Kleigrewe, K., Beyer, M., Humpf, H.-U., and Tudzynski, B.
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(2009) Controlled activation of the Cpx system is essential for growth of Yersinia enterocolitica. FEMS Microbiol.Lett., 296: 274-281
Rönnebäumer, K., Sander, G., Shutinoski, B., Schmidt, M. A., and Heusipp, G.
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(2009) Detection and characterization of the fimbrial sfp cluster in enterohemorrhagic Escherichia coli O165:H25/NM isolates from humans and cattle. Appl. Environ. Microbiol., 75: 64-71
Bielaszewska, M., Prager, R., Vandivinit, L., Müsken, A., Mellmann, A., Holt, N. J., Tarr, P.I., Karch, H., and Zhang, W.
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(2009) Differential sensitivity of human leukocyte-derived cell lines to Shiga toxin. Int. J. Med. Microbiol., 299S1: 46, 55
Hoffmann, P., Duvar, S., Ziehr, H., Karch, H., and Müthing, J.
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(2009) Does Botrytis cinerea ignore H2O2-induced oxidative stress during infection? Characterization of Botrytis activator protein 1. Molecular Plant- Microbe Interactions, 22(8): 987-998
Temme, N. and Tudzynski, P.
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(2009) Functional analyses of pilin-like proteins from Francisella species: complementation of Type IV pilus phenotypes in Neisseria gonorrhoeae. Microbiology, 155: 2546-2559
Salomonsson, E., Forsberg, A., Roos, N., Holz, C., Maier, B., Koomey, M., and Winther- Larsen, H. C.
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(2009) Molecular characterization of a novel Staphylococcus aureus surface protein (SasC) involved in cell aggregation and biofilm accumulation. PLoS ONE, 4(10): e7567
Schroeder, K., Jularic, M., Horsburgh, S.M., Hirschhausen, N., Neumann, C., Bertling, A., Schulte, A., Foster, S.J., Kehrel, B.E., Peters, G., and Heilmann, C.
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(2009) Regulation of major efflux transporters under inflammatory conditions at the blood-brain barrier in vitro. J. Neurochem., 111: 111-118
Von Wedel-Parlow, M., Wölte, P., and Galla, H. J.
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(2009) Simultaneous mechanical stiffness and electrical potential measurements of living vascular endothelial cells using combined atomic force and epifluorescence microscopy. Nanotechnology, 20(17): 175104
Callies, C., Schoen, P., Liashkovich, I., Stock, C., Kusche-Vihrog, K., Fels, J., Straeter, AS., and Oberleithner, H.
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(2009) Stable, non-destructive immobilization of native nuclear membranes to microstructured PDMS for single-molecule force spectroscopy. ChemPhysChem., 10(9 10): 1553-1558
Rangl, M., Nevo, R., Liashkovich, I., Shahin, V., Reich, Z., Ebner, A., and Hinterdorfer, P.
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(2009) Structure and function relationship of the autotransport and proteolytic activity of EspP from Shiga toxin-producing Escherichia coli. PLoS ONE, 4(7):e6100
Brockmeyer, J., Spelten, S., Kuczius, T., Bielaszewska, M., and Karch, H.
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(2010) A novel staphylococcal internalization mechanism involves the major autolysin Atl and heat shock cognate protein Hsc70 as host cell receptor. Cell. Microbiol., 12: 1746-1764
Hirschhausen, N., Schlesier, T., Schmidt, M. A., Götz, F., Peters, G., and Heilmann, C.
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(2010) Application of TLC-IR-MALDI-o-TOF mass spectrometry to structural analysis of bacteria-binding glycosphingolipids selected by affinity detection. Rapid Commun. Mass Spectrom., 24: 1032-1038
Müsken, A., Souady, J., Dreisewerd, K., Zhang, W., Distler, U., Peter-Katalini, J., Miller- Podraza, H., Karch, H., and Müthing, J.
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(2010) Caspase-9-dependent decrease of nuclear pore channel hydrophobicity is accompanied by nuclear envelope leakiness. Nanomedicine., 6(5): 605-611
Kramer, A., Liashkovich, I., Oberleithner, H., and Shahin, V.
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(2010) FfVel1 and FfLae1, components of a velvet-like complex in Fusarium fujikuroi, affect differentiation, secondary metabolism and virulence. Mol. Microbiol., 77(4): 972-994
Wiemann, P., Brown, D.W., Kleigrewe, K., Bok, J.W., Keller, N.P., Humpf, H.-U., and Tudzynski, B.
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(2010) MAP kinase-activated protein kinases 2 and 3 are required for influenza A virus propagation and act via inhibition of PKR. FASEB J., 24(10): 4068-4077
Luig, C., Köther, K., Dudek, S. E., Gaestel, M., Hiscott, J., Wixler, V., and Ludwig S.
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(2010) Multiple pilus motors cooperate for persistent bacterial movement in two dimensions. Phys. Rev. Lett. 104: 178104
Holz, C., Opitz, D., Greune, L., Kurre, R., Koomey, M., Schmidt, M. A., and Maier, B.
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(2010) Neutral glycosphingolipids in human blood: a precise mass spectrometry analysis with special reference to lipoprotein-associated Shiga toxin receptors. J. Lipid Res., 51:2282-2294
Schweppe, C. H., Hoffmann, P., Nofer, J. R., Pohlentz, G., Mormann, M., Karch, H., Friedrich, A. W., and Müthing, J.
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(2010) On the structural diversity of Shiga toxin glycosphingolipid receptors in lymphoid and myeloid cells determined by nanoelectrospray ionization tandem mass spectrometry. Rapid Commun. Mass Spectrom., 24: 2295-2304
Hoffmann, P., Hülsewig, M., Duvar, S., Ziehr, H., Mormann, M., Peter-Katalinić, J., Friedrich, A. W., Karch, H., and Müthing, J.
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(2010) The clinically approved proteasome inhibitor PS-341 efficiently blocks influenza virus propagation via a NF-κB-dependent priming of the type I IFN response. J. Virol., 84(18): 9439-9451
Dudek, S. E., Luig, C., Pauli, E. K., Schubert, U., and Ludwig, S.
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(2010) Transcriptional regulation of the Yts1 Type-II secretion systems of Yersinia enterocolitica and identification of secretion substrates. Mol. Microbiol., 75: 676-691
Shutinoski, B., Schmidt, M. A., and Heusipp, G.
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(2011) Exceptional structural and mechanical flexibility of the nuclear pore complex. J. Cell Physiol., 226(3): 675-682
Liashkovich, I., Meyring, A., Kramer, A., and Shahin, V.
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(2011) Neutrophils cross the BBB primarily on transcellular pathways: An in vitro study. Brain Res., 1367: 62-76
von Wedel-Parlow, M., Schrot, S., Lemmen, J., Treeratanapiboon, L., Wegener, J. and Galla, H.-J.
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(2011) Nuclear delivery mechanism of herpes simplex virus type 1 genome. J. Mol. Recognit., 24(3): 414-421
Liashkovich, I., Hafezi, W., Kühn, J. M., Oberleithner, H., and Shahin, V.
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(2012) BcATF1 – A global regulator controls various differentiation processes and phytotoxin production in Botrytis cinerea. Mol. Plant Pathol., 13: 704-718
Temme, N., Oeser, B., Massaroli, M., Heller, J., Simon, A., Gonzalez Collado, I., Viaud, M., and Tudzynski, P.
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(2012) Biosynthesis of fusarubins accounts for pigmentation of Fusarium fujikuroi perithecia. Appl. Environ. Microbiol., 78(12): 4468-4480
Studt. L., Wiemann, P., Kleigrewe, K., Humpf, H. U., and Tudzynski, B.
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(2012) Characterization of the modular design of the autolysin/adhesin Aaa from Staphylococcus aureus. PLoS One; 7, 2012:e40353
Hirschhausen, N., Schlesier, T., Peters, G., and Heilmann, C.
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(2012) Segregation of secondary metabolite biosynthesis in hybrids of Fusarium fujikuroi and Fusarium proliferatum. Fungal Genet. Biol., 249(7): 567-577
Studt, L., Troncoso, C., Gong, F., Hedden, P., Toomajian, C., Leslie, J. F., Humpf, H. U., Rojas, M. C., and Tudzynski, B.
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(2012) Shiga toxin glycosphingolipid receptor expression and toxin susceptibility of human pancreatic ductal adenocarcinomas of differing origin and differentiation. Biol. Chem., 393:785-799
Storck, W., Meisen, I., Gianmoena, K., Pläger, I., Kouzel, I. U., Bielaszewska, M., Haier, J., Mormann, M., Humpf, H. U., Karch, H., and Müthing, J.
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(2012) Structural organization of the nuclear pore permeability barrier. J. Control. Release., 160(3): 601-608
Liashkovich, I., Meyring, A., Oberleithner, H., and Shahin, V.
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(2012) The Sfp-type 4'-phospho-pantetheinyl transferase Ppt1 of Fusarium fujikuroi controls development, secondary metabolism and pathogenicity. PLoS One, 7(5):e37519
Wiemann, P., Albermann, S., Niehaus, E. M., Studt, L., von Bargen, K. W., Brock, N. L., Humpf, H. U., Dickschat, J. S., and Tudzynski, B.
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(2012) Type II secretion in Yersinia – a secretion system for pathogenicicy and environmental fitness. Front. Cell. Inf. Microbiol., 2: 160
von Tils, D., Blädel, I., Schmidt, M. A., and Heusipp, G.
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(2013) Annexin A6-balanced late endosomal cholesterol controls influenza A replication and propagation. MBio 4: e00608-00613
Musiol, A., Gran, S., Ehrhardt, C., Ludwig, S., Grewal, T., Gerke, V., and Rescher, U.
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(2013) Association of Shiga toxin glycosphingolipid receptors with membrane microdomains of toxin-sensitive lymphoid and myeloid cells. J Lipid Res, 54: 692-710
Kouzel, I., Pohlentz, G., Strock, W., Radamm, L., Hoffmann, P., Bielaszewska, M., Bauwens, A., Cichon, C., Schmidt, M. A., Mormann, M., Karch, H., and Müthing, J.
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(2013) Constitutive androstane receptor upregulates Abcb1 and Abcg2 at the blood-brain barrier after CITCO activation. Brain Res., 1501: 68-80
Lemmen, J., Tozakidis, I.E.P., Bele, P., and Galla, H. J.
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(2013) Early Staphylococcus aureus-induced changes in endothelial barrier funciton are strain-specific and unrelated to bacterial translocation. Int. J. Med. Microbiol., 303:635-644
Kramko, N., Sinitsi, D., Seebach, J., Löffler, B., Dieterich, P., Heilmann, C., Peters, G., and Schnittler, H. J.
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(2013) Expression of Shiga toxin 2e glycosphingolipid receptors of primary porcine brain endothelial cells and toxin-mediated breakdown of the blood-brain barrier. Glycobiology, 23:745-759
Meisen, I., Rosenbrück, R., Galla, H. J., Hüwel, S., Kouzel, I. U., Mormann, M., Karch, H., and Müthing, J.
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(2013) Molecular characterization of the NADPH oxidase complex in the Ergot fungus Claviceps purpurea: CpNox2 and CpPls1 are important for a balanced host-pathogen interaction. Mol. Plant-Microbe Interact., 26: 1151-1164
Schürmann, J., Buttermann, D., Herrmann, A., Giesbert, S., and Tudzynski, P.
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(2013) Pregnane X receptor upregulates ABC-transporter Abcg2 and Abcb1 at the blood-brain barrier. Brain Res., 1491: 1-13
Lemmen, J., Tozakidis, I. E. P., and Galla, H. J.
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(2013) Signaling Governed by G Proteins and cAMP Is Crucial for Growth, Secondary Metabolism and Sexual Development in Fusarium fujikuroi. PLoS One, 8, e58185
Studt, L., Humpf, H.-U., and Tudzynski, B.
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(2013) Two histone deacetylases, FfHda1 and FfHda2, are important for Fusarium fujikuroi secondary metabolism and virulence. Appl. Environ. Microbiol., 79(24):7719-7734
Studt, L., Schmidt, F. J., Jahn, L., Sieber, C. M., Connolly, L. R., Niehaus, E. M., Freitag, M., Humpf, H. U., and Tudzynski, B.
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(2014) Avian influenza viruses inhibit the major cellular signalling integrator c-Abl. Cell. Microbiol., 16: 1854-1874
Hrincius, E. R., Liedmann, S., Anhlan, D., Wolff, T., Ludwig, S., and Ehrhardt, C.
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(2014) Conversion of the Pseudomonas aeruginosa Quinolone Signal and Related Alkylhydroxyquinolines by Rhodococcus sp. Strain BG43. Appl. Environ. Microbiol., 80(23): 7266-7274
Müller, C., Birmes, F. S., Niewerth, H., and Fetzner, S.
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(2014) Large scale RNAi reveals the requirement of nuclear envelope breakdown for nuclear import of human papillomaviruses. PLoS Pathog., 10, e1004162
Aydin, I., Weber, S., Snijder, B., Samperio Ventayol, P., Kühbacher, A., Becker, M., Day, P.M., Schiller, J.T., Kann, M., Pelkmans, L., Helenius, A., Schelhaas, M.
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(2014) MAPKAP kinase 3 suppresses Ifng gene expression and attenuates NK cell cytotoxicity and Th1 CD4 T-cell development upon influenza A virus infection. FASEB J., 28(10):4235-4246
Köther, K., Nordhoff, C., Masemann, D., Varga, G., Bream, J. H., Gaestel, M., Wixler, V., and Ludwig, S.
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(2014) Nanovisualization of viral DNA breaching the nucleocytoplasmic barrier. J. Control. Release., 173:96-101
Meyring-Wösten, A., Hafezi, W., Kühn, J., Liashkovich, I., and Shahin V.
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(2014) New virulence determinants contribute to the enhanced immune response and reduced virulence of an influenza A virus A/PR8/34 variant. J. Infect. Dis., 209: 532-541
Liedmann, S., Hrincius, E. R., Anhlan, D., McCullers, J. A., Ludwig, S., and Ehrhardt, C.
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(2014) Progress in detection and structural characterization of glycosphingolipids in crude lipid extracts by enzymatic phospholipid disintegration combined with thin-layer chromatography immunodetection and IR-MALDI mass spectrometry. Anal. Chem., 86: 1215-1222
Kouzel, I. U., Pirkl, A., Pohlentz, G., Soltwisch, J., Dreisewerd, K., Karch, H., and Müthing, J.
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(2014) Redox systems in Botrytis cinerea: impact on development and virulence. Mol Plant-Microbe Interact., 27: 858-874
Viefhues, A., Heller, J., Temme, N., and Tudzynski, P.
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(2014) Small GTPase-associated signaling by the guanine nucleotide exchange factors CpDock180 and CpCdc24, the GTPase effector CpSte20 and the scaffold CpBem1 in Claviceps purpurea. Eukaryotic Cell 13:470-482
Herrmann, A., Tillmann, B., Schürmann, J., Boelker, M., and Tudzynski, P.
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(2014) The Rac1 inhibitor NSC23766 exerts anti-influenza virus properties by affecting the viral polymerase complex activity. PLoS One 9: e88520
Dierkes, R., Warnking, K., Liedmann, S., Seyer, R., Ludwig, S., and Ehrhardt, C.
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(2014) Unravelling crucial biomechanical resilience of myelinated peripheral nerve fibres provided by the Schwann cell basal lamina and PMP22. Sci. Rep., 4:7286
Rosso, G., Liashkovich, I., Gess, B., Young, P., Kun, A., and Shahin, V.
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(2014) Viral suppressors of the RIG-I-mediated interferon response are pre-packaged in influenza virions Nature Comm., 5: 5645
Liedmann, S., Hrincius, E. R., Guy, C., Anhlan, D., Dierkes, R., Carter, R., Wu, G., Staeheli, P., Green, D. R., Wolff, T., McCullers, J. A., Ludwig, S., and Ehrhardt, C.
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. (2014) Rabbit monoclonal antibodies directed at the T3SS effector protein YopM identify human pathogenic Yersinia isolates. Int. J. Med. Microbiol., 304: 444-451.n
Rüter, C., Ruiz Silva, M., Lubos, M.-L., Scharnert, J., Grabowski, B., Poceva, M., von Tils, D., Flieger, A., Heesemann, J., Bliska, J. B., and Schmidt, M. A.
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(2015) Biotic inactivation of the Pseudomonas aeruginosa quinolone signal molecule. Environ. Microbiol.,17(11): 4352-4365
Soh, E. Y., Chhabra, S. R., Halliday, N., Heeb, S., Müller, C., Birmes, F. S., Fetzner, S., Cámara, M., Chan, K. G., and Williams, P.
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(2015) Clathrin inhibitor Pitstop-2 disrupts the nuclear pore complex permeability barrier. Sci. Rep., 5:9994
Liashkovich, I., Pasrednik, D., Prystopiuk, V., Rosso, G., Oberleithner, H., and Shahin, V.
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(2015) Nonstructural protein 1 (NS1)-mediated inhibition of c-Abl results in acute lung injury and priming for bacterial coinfections: insights into 1918 H1N1 pandemic? J. Infect. Dis., 211(9):1418-28
Hrincius, E. R., Liedmann, S., Finkelstein, D., Vogel, P., Gansebom, S., Ehrhardt, C., Ludwig, S., Hains, D. S., Webby, R., and McCullers, J. A.
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(2015) Shiga toxin glycosphingolipid receptors of Vero-B4 kidney epithelial cells and their membrane microdomain lipid environment. J. Lipid Res., 56(12): 2322-2336
Steil, D., Schepers, C. L., Pohlentz, G., Legros, N., Runde, J., Humpf, H. U., Karch, H., and Müthing, J.
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(2015) Unraveling the function of the response regulator BcSkn7 in the stress signaling network of Botrytis cinerea. Eukaryot. Cell., 14(7): 636-651
Viefhues, A., Schlathoelter, I., Simon, A., Viaud, M., and Tudzynski, P.
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(2016) Interplay between pathway-specific and global regulation of the fumonisin gene cluster in the rice pathogen Fusarium fujikuroi. Appl. Microbiol. Biotechnol.
Rösler, S. M., Sieber, C. M., Humpf, H. U., and Tudzynski, B.
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(2016) Shiga toxin of enterohaemorrhagic Escherichia coli directly injures developing human erythrocytes. Cell. Microbiol.
Betz, J., Dorn, I., Kouzel, I. U., Bauwens, A., Meisen, I., Kemper, B., Bielaszewska, M., Mormann, M., Weymann, L., Sibrowski, W., Karch, H., Schlenke, P., and Müthing, J.