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Project 3
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Project 3

Albert Haas

Molecular analysis of the interaction between pathogenic Rhodococcus equi and their host macrophages

Institute for Cell Biology, University Bonn


Brief description in German:
Wenn Mikroorganismen in den sterilen Bereich höherer Organismen gelangen, werden sie normalerweise von Fresszellen (z.B. Makrophagen) aufgenommen, getötet und verdaut. Einige spezialisierte Pathogene, darunter Rhodococcus equi, mißbrauchen Makrophagen als Ort ihrer Vermehrung und erzeugen schwere Erkrankungen. Sie funktionieren Makrophagen so um, dass sie nicht mit deren Tötungs- und Abbauapparat in Berührung kommen und sich in ihnen vermehren können. Welche Mechanismen dem zugrunde liegen und wie Makrophagen dennoch unter gewissen Umständen autonom Rhodokokken töten, ist Gegenstand unserer Forschung.

Microorganisms that reach the sterile sections of higher organisms are usually quickly ingested by phagocytes (e.g., macrophages), killed and degraded. Killing, as a basically cell-autonomous function, occurs mostly in a phagolysosome which is formed when the particle-containing compartment (phagosome) fuses with acidic lysosomes.

Some specialised pathogens, e.g., bacteria of the species Rhodococcus equi can, however, reprogram phagosome development and multiply in macrophages although these had evolved to destroy microorganisms. R. equi is a zoonotic pathogen which causes a tuberculosis-like illness in young foals and immune-suppressed humans.

Our studies have shown that macrophage phagosomes containing virulent R. equi are arrested in their maturation at a pre-lysosomal stage, that the phagosomes are neutral in pH and lack lysosomal hydrolases. The pathogens multiply in this privileged compartment and the host cell is eventually destroyed by necrosis. All of these pathogenetically relevant features are regulated by a rhodococcal virulence-associated plasmid.

The proposed project describes a study aimed at understanding (1) the mechanisms by microbial factors reprogramme phagosome trafficking in macrophages, (2) the mechanisms by which R. equi can exclude incorporation of the H+-ATPase complex that is crucial for phagosome acidification and cell-autonomous immune functions, and (3) how a pathogen’s host specificity may be "encoded" at the level of its interaction with macrophages.

List of publications resulting from the project
Peer-reviewed publications:

Geerds, C., Wohlmann, J., Haas, A., Niemann, H.H. (2014) Structure of Rhodococcus equi virulence-associated protein B (VapB) reveals an eight-stranded antiparallel β-barrel consisting of two Greek-key motifs. Acta Crystallogr F Struct Biol Commun 70, 866-871

Sydor, T., von Bargen, K., Hsu, F.F., Huth, G., Holst, O., Wohlmann, J., Becken, U., Dykstra, T., Söhl, K., Lindner, B., Prescott, J.F., Schaible, U.E., Utermöhlen, O., Haas, A. (2013) Diversion of phagosome trafficking by pathogenic Rhodococcus equi depends on mycolic acid chain length. Cell Microbiol 15, 458-473.

Hilbi, H., Haas, A. (2012) Secretive bacterial pathogens and the secretory pathway. Traffic 13, 1187-1197.

Hsu, F.F., Wohlmann, J., Turk, J., Haas, A. (2011) Structural definition of trehalose 6-monomycolates and trehalose 6,6'-dimycolates from the pathogen Rhodococcus equi by multiple-stage linear ion-trap mass spectrometry with electrospray ionization. J Am Soc Mass Spectrom 22, 2160-2170.

von Bargen, K., Wohlmann, J., Taylor, G.A., Utermöhlen, O., Haas, A. (2011) Nitric oxide-mediated intracellular growth restriction of pathogenic Rhodococcus equi can be prevented by iron. Infect Immun 79, 2098-2111

Hsu, F.F., Soehl, K., Turk, J., Haas, A. (2011) Characterization of mycolic acids from the pathogen Rhodococcus equi by tandem mass spectrometry with electrospray ionization. Anal Biochem 409, 112-122.

Becken, U., Jeschke, A., Veltman, K., Haas, A. (2010) Cell-free fusion of bacteria-containing phagosomes with endocytic compartments. Proc Natl Acad Sci USA 107, 20726-20731

Non peer-reviewed publications:
Schaible, U. E. and Haas, A. (eds) (2009): Intracellular Niches of Microorganisms – a pathogen’s guide through the host cell. WILEY-BLACKWELL Press, 712 pp., ISBN-10: 3-527-32207-8.

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