So-called ubiquitins can play an important role during bacterial infections. Are they suitable for new therapeutic approach?

What is this research project about?

Diagram of implant-associated infections

What is this research project about?

The risk and the course of serious bacterial infections are primarily determined by the interaction between the specific bacterium and the infected human. The susceptibility to infection is critically determined by individual host-specific factors including an underlying immunodeficiency, the age and the existence of implants. Bacterial pathogens exploit the impaired resistance of humans to cause infections. At the same time, practically all relevant bacterial pathogens actively weaken the immune system of the infected individuals and thereby exacerbate the infection. Due to the increasing antibiotic resistance of bacteria, antibiotic therapy becomes more challenging. In this regard, the prevention of an impairment of the immune system and its strengthening constitute an innovative therapeutic option.

What’s the current status?

In order to rapidly sense pathogens, the immune system possesses several receptors which identify invading bacteria. Upon engagement of these receptors, defense mechanisms are activated swiftly in immune cells which trigger antibacterial immune reactions within minutes. These immune reactions are decisively dependent on the posttranslational modification of host cell proteins. This includes the ubiquitination of host cell proteins by either the accumulation of ubiquitin molecules on the protein or the cleavage of ubiquitin molecules. In both acute and chronic infections, the ubiquitination status of immunologically important signaling molecules in infected cells and leukocytes is of fundamental importance for the course of infection. For this reason, numerous bacteria have developed mechanisms to manipulate the ubiquitination of host proteins. A therapeutic manipulation of the ubiquitination processes potentially offers new treatment options of infectious diseases beyond antibiotics.

What are the project goals?

A prerequisite for the development of novel therapeutics influencing the ubiquitination status of host signaling molecules is a profound understanding of the immunological function of ubiquitin attaching and cleaving proteases in bacterial infections. A combined effort on experimental and clinical studies will allow the identification of particularly important ubiquitin regulating host cell proteins. These studies will also provide the basis for the targeted development of therapeutics strengthening the antibacterial immune response by ubiquitin modifications.

How do we get there?

In order to evaluate the potential of ubiquitin modulating substances as antiinfectives, we will continue our work on the functional significance and individual domains of deubiquitinating enzymes (DUBs). We have already performed corresponding investigations on the DUBs TNFAIP3, CYLD and OTUB1 and we identified specific domains of these DUBs, which mediate the successful control of bacterial infections (Just et al., 2016; Wex et al., 2016; Wang et al., 2013; Wang et al., 2019; Nishanth et al., 2013). To further study structure/function relation of DUBs, we currently generate new innovative mouse models. In these experiments, we will use established experimental infection models such as listeriosis and additional new models of Staphylococcus aureus-infected implants. Additionally, we will extend these studies to ubiquitin-conjugating enzymes such as the E3-ligase SOCS2. In parallel, we will characterize the expression profile of the 100 known DUBs in samples of human implant-associated infections (cooperation with Prof. Stiesch) and in patients with cholangitis (PD Dr. Heidrich). On the basis of these data, we will develop DUB inhibitors directed against the identified immunologically important domains of DUBs and evaluate these inhibitors in the aforementioned model infections.

Projectleaders

Project title: Structural and functional analysis of deubiquitinating enzymes as regulators and therapeutic targets in bacterial infections

Prof. Dr. Dirk Schlüter

Projekt: B12

  Leiter
  Institut für Medizinische Mikrobiologie und Krankenhaushygiene, Medizinische Hochschule Hannover
  Carl-Neuberg-Str. 1
30625 Hannover
  +49 511 532-6770
  +49 511 532-4355
 
  Schlueter.Dirk
@mh-hannover.de
  DOWNLOAD CV

Project B12 Publications

X. Wang, F. Mulas, W Yi, A. Brunn, G. Nishanth, S. Just, A. Waisman, W. Brück, M. Deckert, D. Schlüter (2019) The deubiquitinase OTUB1 inhibits central nervous system autoimmunity by preventing IFN-γ-induced hyperactivation of astrocytes through stabilization of SOCS1. EMBO J e100947. DOI: 10.15252/embj.2018100947.

M.C.C. Lim, G. Maubach G, O. Sokolova, M.H. Feig, R. Diezko, J. Buchbinder, S. Backert, D. Schlüter, I.N. Lavrik, Naumann M. (2017) Pathogen-induced ubiquitin editing enzyme A20 bifunctionally shuts off NF-kB and caspase 8-dependent apoptotic cell death. Cell Death Diff 24:1621-1631.

U. Schmid, W. Stenzel, J. Koschel, M. Raptaki, X. Wang, M. Naumann, K. Matuschewski, D. Schlüter, G. Nishanth. (2017) The Deubiquitinating Enzyme Cylindromatosis Dampens CD8(+) T Cell Responses and Is a Critical Factor for Experimental Cerebral Malaria and Blood-Brain Barrier Damage. Front Immunol 8:27. doi: 10.3389/fimmu.2017.00027.

S. Just, G. Nishanth, J. Buchbinder, X. Wang, M. Naumann, I. Lavrik, D. Schlüter (2016) A20 curtails primary but augments secondary CD8+ T cell responses in intracellular bacterial infection. Sci Rep. 6:39796. doi: 10.1038/srep39796.

K. Wex, U. Schmid, S. Just, X. Wang, R. Wurm, N. Naumann, D. Schlüter, G. Nishanth (2016) Receptor-Interacting Protein Kinase-2 Inhibition by CYLD Impairs Antibacterial Immune Responses in Macrophages. Front. Immunol 6:650. doi: 10.3389/fimmu.2015.00650.

R. Wurm, S. Just, X. Wang, K. Wex, U. Schmidt, N. Blanchard, A. Waisman, H. J. Schild, M. Deckert, M. Naumann, D. Schlüter, G. Nishanth (2015) protective immune responses against listeriosis induced by the short form of the deubiquitinating enzyme CYLD are inhibited by full-length. Eur J Immunol 45:1366-1376.

N. T. Xuan, X. Wang, G. Nishanth, A. Waisman, K. Borucki, B. Isermann, M. Naumann, M. Deckert, D. Schlüter (2015) A20 expression in dendritic cells protects against LPS-induced mortality. Eur J Immunol 45:818-828.

G. Nishanth, M. Deckert, K. Wex, R. Massoumi, K. Schweitzer, M. Naumann, D. Schlüter. 2013. CYLD enhances severe listeriosis by impairing IL-6/STAT3-dependent fibrin production. PLoS Pathogens 9(6): e1003455. doi10.1371/journal.ppat.1003455.

Project B12
Publications