Kliniken & Institute ... Institute Zentrum für... Medizinische... Forschung Research Kubatzky

Signal Transduction of the Pasteurella multocida toxin (PMT):

PMT is highly mitogenic and has potential carcinogenic properties. PMT causes a respiratory disease, atrophic rhinitis, that is characterized by bone resorption and loss of nasal turbinates. Pasteurella multocida infections mainly affect swine, cattle and sheep, but also cats and dogs. Experimental nasal infection induces excess proliferation of bladder epithelial cells. PMT acts intracellularly by constitutively activating the heterotrimeric G proteins Gq and G12/13 through deamidation. We recently found that PMT induces the activation of STAT (signal transducer and activator of transcription) and uses mechanisms known from viral signalling molecules or proto-oncogenes to evade downregulation. In immune cells, PMT targets B cells and macrophages to trigger cellular differentiation into osteoclasts. On a molecular level, PMT-induced ostoclastogenesis is not fully understood. We hypothesise that PMT-triggered osteoclast formation is a mechanism of immune evasion and we aim to identify the molecular pathways in our studies.

Prof. Dr. Hermanns, LMU München

Pateurella multocida toxin as a tool to modulate bone and immune cell differentiation:

The project will investigate the connection between B-cell and osteoclast differentiation, using the bacterial toxin from Pasteurella multocida (PMT) as a model system. PMT is a potent mitogen with known osteoclastic properties that stimulates differentiation of bone marrow cells into osteoclasts and inhibits osteoblast function, respectively. The aim of the project is to further elucidate the mechanism of PMT-induced osteoclast differentiation and to define the role of B-cells in that process. We aim to characterise the PMT-generated B-cell and osteoclast populations and their interaction or dependence of each other. We will investigate the mechanism of that interaction on a molecular level by characterising the secreted factors and by comparing the secretome and proteome of PMT and IL7, M-CSF/RANKL or LPS derived osteoclasts. In addition, we aim to define the signalling networks involved in the interplay between B-cells and osteoclasts, with a focus on anti-apoptotic signalling through Akt and Pim kinases and the importance of migration and adhesion to further expand our understanding of the regulation of bone destruction by immunological processes.

SPP1468 Immunobone

Selected publications:

Chakraborty S, Kloos B, Roetz N, Schmidt S, Eigenbrod T, Kamitani S, Kubatzky KF. 2018
Influence of Pasteurella multocida Toxin on the differentiation of dendritic cells into osteoclasts.
Immunobiology. 2018 Jan;223(1):142-150.

Chakraborty S, Kloos B, Harre U, Schett G, Kubatzky KF. 2017
Pasteurella multocida Toxin Triggers RANKL-Independent Osteoclastogenesis.
Front Immunol. 2017 Feb 27;8:185.

Sastalla I, Monack DM, Kubatzky KF. 2016
Bacterial Exotoxins: How Bacteria Fight the Immune System.
Front Immunol. 2016 Aug 2;7:300.

Hildebrand D, Heeg K, Kubatzky KF. 2015
Pasteurella multocida Toxin Manipulates T Cell Differentiation.
Front Microbiol. 6:1273 (2015).

Kloos B, Chakraborty S, Lindner SG, Noack K, Harre U, Schett G, Krämer OH, Kubatzky KF. 2015
Pasteurella multocida toxin- induced osteoclastogenesis requires mTOR activation.
Cell Commun Signal. 13:40 (2015).

Hildebrand D, Bode KA, Rieß D, Cerny D, Waldhuber A, Römmler F, Strack F, Korten S, Orth JH, Miethke T, Heeg K, Kubatzky KF. 2014
Granzyme A Produces Bioactive IL-1ß through a Nonapoptotic Inflammasome-Independent Pathway.
Cell Rep. 9(3): 910-917

Kubatzky KF, Kloos B, Hildebrand D. 2013
Signaling Cascades of Pastereulla multocida Toxin in Immune Evasion.
Toxins. 5(9): 1664-1681

Hildebrand D, Sahr A, Wölfle SJ, Heeg K, Kubatzky KF. 2012
Regulation of Toll-like receptor 4-mediated immune responses through Pasteurella multocida toxin-induced G protein singalling.
Cell Commun Signal. 10(1): 22

Kubatzky KF. 2012
Pasteurella multocida and immune cells.
Curr Top Microbiol Immunol. 361: 53-72

Hildebrand D, Heeg K, Kubatzky KF. 2011
Pateurella multocida toxin-stimulated osteoclast differentiation is B cell dependent.
Infect Immun. 79(1): 220-228

Hildebrand D, Walker P, Dalpke A, Heeg K, Kubatzky KF. 2010 >br />Pasteurella multocida Toxin-induced Pim-1 expression disrupts suppressor of cytokine signalling (SOCS)-1 activity.
Cell Microbiol. 12(12): 1732-1745

Preuss I, Hildebrand D, Orth JH, Aktories K, Kubatzky KF. 2010
Pasteurella multocida toxin is a potent activator of anti-apoptotic signalling pathways.
Cell Microbiol. 12(8): 1174-1185

Orth JH, Aktories K, Kubatzky KF. 2007
Modulation of host cell gene expression through activation of STAT transcription factors by Pasteurella multocida toxin.
J Biol Chem. 282(5): 3050-3057