Forschung

Direkt zum Inhalt | Direkt zur Navigation

Benutzerspezifische Werkzeuge

Sektionen
AG Plum
Sie sind hier: Startseite / Forschung / AG Plum

AG Plum

Group Leader: Priv. Doz. Dr. Georg Plum
Contact: Oberarztsekretariat Marion Peters
Phone: +49 221 478-32009
E-Mail: [Email protection active, please enable JavaScript.]

Selected recent publications

Co-workers:
Contact: +49 221 478-32100
Lisa Hofmann
Nicole Nissen
Ines Osmialowski
Pia Wiegel
Ruben Willmes
Martina Wolke

Cooperations:
Dr. Pia Hartmann, Dr. Jan Rybniker, 1st Department of Internal Medicine, Division of Infectious Diseases
Dr. Nikoletta Papadopoulou, Institute for Medical Microbiology, Immunology und Hygiene, University of Cologne
Dr. Thomas Kolter, Kekulé Institute for Organic Chemistry, University of Bonn


Brief description in German:
Forschungsziele

Meine Arbeitsgruppe forscht an der Aufklärung von Virulenzeigenschaften intrazellulärer Bakterien, insbesondere der Mykobakterien (z.B. Mycobacterium tuberculosis, M. avium, M. marinum). Diese Bakterien haben im Laufe der Evolution die Fähigkeit optimiert, nach dem Eindringen in den Körper ihres Wirtsorganismus, vom Immunsystem unbehelligt zu bleiben und sich in dessen Zellen langsam zu vermehren.

Die Moleküle, die von den Bakterien ausgehen und das Immunsystem des Wirts so beeinflussen, dass sie nicht abgetötet werden, sind erst unvollständig erforscht. Sie sind jedoch langfristig als lohnende Ziele für die Entwicklung von Arzneimitteln und Impfstoffen zur Behandlung der Erkrankung Tuberkulose von großem Interesse.

Als experimentelle Methoden setzen wir dazu gentechnische Verfahren zur Expression und Analyse von mykobakteriellen Genen und zellbiologische Verfahren zur Bestimmung der immunologischen Reaktion der Wirtszelle in einem Zellkulturinfektionsmodell ein.

In einem weiteren Bereich arbeiten wir mit außer- und inneruniversitären Partnern an der Verbesserung der molekularbiologischen Verfahren zum Nachweis von Krankheitserregern in klinischem Untersuchungsmaterial.


Research topic:

Identification and characterization of mycobacterial genes required for intracellular survival in macrophages
Virulent mycbacteria (e.g. M. tuberculosis, M. avium and also including M. marinum) are readily phagozytosed by host macrophages. However, the resultant phagosomes do not fuse with lysosomes. The precise molecular mediators for the phagosome maturation inhibition remain to be elucidated.

The complexity of the mycobacterial metabolism and its components are a major obstacle that impede direct identification of the molecules responsible for virulence. This situation asks for a genetic screen to uncover the genes essential for a virulent phenotype.

We have generated a transposon mutant library of the virulent mycobacterial species M. marinum to address this question. Within the family Mycobacteriaceae this species is phylogenetically most closely related to M. tuberculosis. In the immunocompetent human host it occasionally causes skin infection that is usually self limiting and is described as "swimming pool granuloma" or "fish tank granuloma".

On histological examination the granuloma caused by a M. marinum dermal infection in humans is very similar to that caused by a M. tuberculosis lung infection. We have applied a highly efficient transposon mutagenesis system to generate a random mutant library of M. marinum covering the entire genome.

Screening of our library in a phagosome maturation assay allowed us to identify mutants that no longer are able to prevent phagosome maturation. The majority of the mutants with defects in phagosome maturation inhibition showed a defect in expressing specific glycolipids of the mycobacterial cell envelope.

One of these lipids was identified as phenolic glycolipid (PGL) and we were able to prove that PGL alone can prevent phagosome maturation in primary human macrophages when it is coated onto the surfaces of inert microbeads or microbial cells which are otherwise unable to prevent phagosome maturation. A second immunologically important feature of this lipid is its strong ability to block pro-inflammatory cytokine release from the infected cell.

Outlook:
We are currently involved in experiments to elucidate the mechanisms of phagosome maturation inhibition and pro-inflammatory cytokine blockade by PGL and closely related mycobacterial lipids. Experimentally we follow the changes induced by PGL in the TLR-, NOD-, IRF-, C-type lectin pathways to identify the molecules where PGL interferes with the intracellular signalling cascades.

Perspectives:
The identification and analysis of the function of genes responsible for the evasion of the phagolysosomal fusion will potentially lead to the development of effective therapeutics for prophylaxis or treatment of mycobacterial infection.

Selected recent publications (2005 - date)
Rybniker, J., Nowag, A., van Gumpel, E., Nissen, N., Robinson, N., Plum, G., Hartmann, P. (2010) Insights into the function of the WhiB-like protein of mycobacteriophage TM4--a transcriptional inhibitor of WhiB2. Mol Microbiol 77(3): 642-57.

Kalka-Moll, W. M., J. J. LiPuma, F. J. Accurso, G. Plum, S. van Koningsbruggen and P. Vandamme. (2009) Airway infection with a novel Cupriavidus species in persons with cystic fibrosis. J Clin Microbiol 47(9): 3026-8.

Sankar, T. S., G. Neelakanta, V. Sangal, G. Plum, M. Achtman and K. Schnetz. (2009) Fate of the H-NS-repressed bgl operon in evolution of Escherichia coli. PLoS Genet 5(3): e1000405.

Robinson, N., T. Kolter, M. Wolke, J. Rybniker, P. Hartmann and G. Plum. (2008) Mycobacterial phenolic glycolipid inhibits phagosome maturation and subverts the pro-inflammatory cytokine response. Traffic 9(11): 1936-47.

Rybniker, J., G. Plum, N. Robinson, P. L. Small and P. Hartmann. (2008) Identification of three cytotoxic early proteins of mycobacteriophage L5 leading to growth inhibition in Mycobacterium smegmatis. Microbiology 154(Pt 8): 2304-14.

Dörbecker, C., C. Licht, F. Körber, G. Plum, C. Haefs, B. Hoppe and H. Seifert. (2007) Community-acquired pneumonia due to Bordetella holmesii in a patient with frequently relapsing nephrotic syndrome. J Infect 54(4): e203-5. Epub 2006 Dec 14.
Robinson, N., M. Wolke, K. Ernestus and G. Plum. (2007) A mycobacterial gene involved in synthesis of an outer cell envelope lipid is a key factor in prevention of phagosome maturation. Infect Immun 75(2): 581-91. Epub 2006 Nov 6.

Simon, A., P. Groneck, B. Kupfer, R. Kaiser, G. Plum, R. L. Tillmann, A. Müller and O. Schildgen. (2007) Detection of bocavirus DNA in nasopharyngeal aspirates of a child with bronchiolitis. J Infect 54(3): e125-7. Epub 2006 Sep 11.

Stephen, T. L., M. Fabri, L. Groneck, T. A. Röhn, H. Hafke, N. Robinson, J. Rietdorf, D. Schrama, J. C. Becker, G. Plum, M. Krönke, H. Kropshofer and W. M. Kalka-Moll. (2007) Transport of Streptococcus pneumoniae Capsular Polysaccharide in MHC Class II Tubules. PLoS Pathog 3(3): e32.

Kupfer, B., J. Vehreschild, O. Cornely, R. Kaiser, G. Plum, S. Viazov, C. Franzen, R.-L. Tillmann, A. Simon, A. Müller and O. Schildgen. (2006) Severe Pneumonia and Human Bocavirus in Adult. Emerging Infectious Diseases 12(10).

Wisplinghoff, H., B. Ewertz, S. Wisplinghoff, D. Stefanik, G. Plum, F. Perdreau-Remington and H. Seifert. (2005) Molecular evolution of methicillin-resistant Staphylococcus aureus in the metropolitan area of Cologne, Germany, from 1984 to 1998. J Clin Microbiol 43(11): 5445-51.

Kalka-Moll, W. M., M. A. Van Bergen, G. Plum, M. Krönke and J. A. Wagenaar. (2005) The need to differentiate Campylobacter fetus subspecies isolated from humans. Clin Microbiol Infect 11(4): 341-2.

zum Seitenanfang