Iris

Immunotherapy against multi-resistant germs
Identification of commensal bacteria-associated immune checkpoints as novel targets for immunotherapy against multidrug-resistant Staphylococcus epidermidis strains

Our immune system is in balance with the body’s own bacterial environment. These so-called commensal bacteria are also essential for the correct functioning of our skin and integrity. Under certain circumstances commensal bacteria can develop resistance against antibiotics and become pathogenic organisms, causing fulminant and almost uncontrollable infections. Therefore, it is of central importance to identify the so far unknown interactions between microorganisms immune system orchestrating tolerance and host defense.

Based on the expected data we will be able to encrypt and modulate the immune response against pathogenic and commensal bacteria.

Strategy and conditions

In order to realize the ambitious project (see goals), we will analyze the interaction between S. epidermidis strains and the host cells to understand both the colonization and transformation to pathogenic strains. This knowledge is essential for the development of future host-based therapies and prevention.

The IRIS team is well prepared for this. The Institute of Microbiology and Hygiene at the University of Regensburg (WP1; Team Gessner) is already a reference center that coordinates various standardization initiatives in the field of microbial analysis in Germany and in the EU. WP1 will perform all bacteria-associated sequence analyses that are crucial for the IRIS-project. Human immune cells will be analyzed after contact with S. epidermidis strains at the Department of Dermatology of the University of Erlangen-Nuremberg (WP2; team Dudziak). This is of central importance to validate data that will be generated with other experimental models.

The Regensburg Center for Interventional Immunology (WP3; RCI-team Feurer/Ritter) has a profound expertise in the fields of immunotolerance and pathogen-host interactions. In addition, various platforms of methods have been established at the RCI, which allows a high-level realization of the project. All three teams have developed extensive know-how in their respective fields of expertise in the analysis and integration of bioinformatics data. These include in particular single cell RNAseq, ATAC analysis and microbiome sequencing data.

Aims of the research project

The aim of IRIS is to understand why the immune system recognizes but tolerates commensal skin bacteria such as S. epidermidis and does not induce defense mechanisms. We intend to specifically break down this immunological tolerance in order to enable protective immunity responses against multi-resistant germs.

Expected benefits for society

With the funded project, we expect to be able to make an important contribution to the development of promising therapeutic approaches, where the immune system is reprogrammed in order to combat multidrug resistant germs. This approach would have the potential benefit of avoiding the use of classical reserve antibiotics, which in turn can trigger resistance. Such an endogenous control of multi-resistant bacteria would play a significant role for the health system and the economy in Bavaria and would have global impact as well.

Team

Prof. Dr. Dr. André Gessner
Project Management

Universität Regensburg
Institut für Mikrobiologie und Hygiene

Prof. Dr. Diana Dudziak
Project Management

Universitätsklinikum Erlangen
Projektleiterin und Sprecherin des Forschungsverbundes

Prof. Dr. Markus Feuerer
Project Management

Regensburger Centrum für Interventionelle Immunologie

Prof. Dr. Uwe Ritter
Project Management

Regensburger Centrum für Interventionelle Immunologie

Universität Regensburg

Universitätsklinikum Erlangen

Cooperations

PD Dr. med. Wilma Ziebuhr, Universität Würzburg, Institut für Molekulare Infektionsbiologie, Universität Würzburg. Emailadresse: w.ziebuhr@mail.uni-wuerzburg.de

PD Dr. rer. nat. Knut Ohlsen, Universität Würzburg, Institut für Molekulare Infektionsbiologie, Universität Würzburg. Emailadresse: knut.ohlsen@uni-wuerzburg.de

Dr. Martin Fraunholz, Lehrstul für Mikrobiologie, Universität Würzburg. Emailadresse: martin.fraunholz@uni-wuerzburg.de

Publications

Delacher M, Imbusch CD, Hotz-Wagenblatt A, Mallm JP, Bauer K, Simon M, Riegel D, Rendeiro AF, Bittner S, Sanderink L, Pant A, Schmidleithner L, Braband KL, Echtenachter B, Fischer A, Giunchiglia V, Hoffmann P, Edinger M, Bock C, Rehli M, Brors B, Schmidl C, Feuerer M. Precursors for Nonlymphoid-Tissue Treg Cells Reside in Secondary Lymphoid Organs and Are Programmed by the Transcription Factor BATF. Immunity, 18;52(2):295-312.e11 (2020).

Delacher M, Schmidl C, Herzig Y, Breloer M, Hartmann W, Brunk F, Kägebein D, Träger U, Hofer AC, Bittner S, Weichenhan D, Imbusch CD, Hotz-Wagenblatt A, Hielscher T, Breiling A, Federico G, Gröne, HJ, Schmid RM, Rehli M, Abramson J, Feuerer M. Rbpj expression in regulatory T cells is critical for restraining TH2 responses. Nature Communications, 8;10:1621 (2019).

Zimara N., Menberework C., Abraham A., van Zandbergen G., Lepenies B., Schmid M., Weiss R., Rascle A., Wege A.K, Jantsch J., Schatz V., Brown G.D and Ritter U. Dectin-1 positive dendritic cells expand after infection with Leishmania major parasites and represent promising targets for vaccine development. Frontiers in Immunology, 26;9:263 (2018).

Zach F, Polzer F, Mueller A, Gessner A. p62/sequestosome 1 deficiency accelerates osteo- clastogenesis in vitro and leads to Paget’s disease-like bone phenotypes in mice. J Biol Chem. 293:9530-9541 (2018).

Lehmann CHK, Baranska A, Heidkamp GF, Heger L, Neubert K, Lühr JJ, Hoffmann A, Reimer K, Brückner, C, Beck S, Seeling M, Kießling M, Soulat D, Krug A, Ravetch JV, Jeanette H. W. Leusen JHW, Nimmerjahn, F, Dudziak D. DC subset specific induction of T cell responses upon antigen uptake via Fcγ receptors in vivo. J. Exp. Med, 214(5):1509-1528 (2017).

Delacher M, Imbusch CD, Weichenhan D, Breiling A, Hotz-Wagenblatt A, Träger U, Hofer AC, Kägebein, D, Wang Q, Frauhammer F, Mallm JP, Bauer K, Herrmann C, Lang PA, Brors B, Plass C, Feuerer M. Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues. Nature Immunology, 18(10):1160-1172 ­(2017).

Herzig Y, Nevo S, Bornstein C, BrezisMR, Ben-Hur S, Shkedy A, Eisenberg-Bord M, Levi B, Delacher M, Goldfarb Y, David E, Weinberger L, Viukov S, Ben-Dor S, Giraud M, Hanna JH, Breiling A, Lyko F, Amit I,Feuerer M, Abramson J. Transcriptional programs controlling the expression of the Autoimmuneregulator gene. Nature Immunology, 18(2):161-172 (2017).

Hiergeist A, Reischl U, Gessner A. Multicenter quality assessment of 16S ribosomal DNA-sequencing for microbiome analyses reveals high inter-center variability. International Journal of Medical Microbiology. 306(5):334–342 (2016).

Asare Y, Ommer M, Azombo FA, Alampour-Rajabi S, Sternkopf M, Sanati M, Gijbels MJ, Schmitz C,Sinitski D, Tilstam PV, Lue H, Gessner A, Lange D, Schmid JA, Weber C, Dichgans M, Jankowski J, Pardi R, de Winther MP, Noels H, Bernhagen J. Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo. Proc Natl Acad Sci U S A.; 114: E2766-E2775 (2017).

Heidkamp GF*, Sander J*, Lehmann CH, Heger L, Eissing N, Baranska A, Lühr JJ, Hoffmann A, Reimer K, Lux A, Söder S, Hartmann A, Zenk J, Ulas T, McGovern N, Alexiou C, Spriewald B, Mackensen A, Schuler, G, Schauf B, Forster A, Repp R, Fasching PA, Purbojo A, Cesnjevar R, Ullrich E, Ginhoux F, Schlitzer A, Nimmerjahn F, Schultze JL*, Dudziak D*. Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment. Sci Immunol, 1: 1-17 (2016).