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

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

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

Publications
  • Antibiotikaresistenzen: Mit Grundlagenforschung und Datenvernetzung gegen die globale Herausforderung
    Kaltenhauser U, Hauser A
    Biotechnologie in Bayern 2022; München, bioM
  • Identification of Antimotilins, Novel Inhibitors of Helicobacter pylori Flagellar Motility That Inhibit Stomach Colonization in a Mouse Model
    Suerbaum S, Coombs N, Patel L, Pscheniza D, Rox K, Falk C, Gruber AD, Kershaw O, Chhatwal P, Brönstrup M, Bilitewski U, Josenhans C
    mbio 2022; 13(2): e0375521
  • Efficacy of Vancomycin and Meropenem in Central Nervous System Infections in Children and Adults: Current Update
    Schneider F, Gessner A, El-Najjar N
    Antibiotics (Basel) 2022; 11(2): 173
  • On microbial syringes: Advances in our understanding of type III secretion systems in bacterial pathogenesis
    Hornef MW, Jantsch J
    Phys Life Rev 2021; 39: 96-98
  • High Na(+) Environments Impair Phagocyte Oxidase-Dependent Antibacterial Activity of Neutrophils
    Krampert L, Bauer K, Ebner S, Neubert P, Ossner T, Weigert A, Schatz V, Toelge M, Schroder A, Herrmann M, Schnare M, Dorhoi A, Jantsch J
    Front Immunol 2021; 12: 712948
  • Sfaira accelerates data and model reuse in single cell genomics
    Fischer DS, Dony L, König M, Moeed A, Zappia L, Heumos L, Tritschler S, Holmberg O, Aliee H, Theis FJ
    Genome Biol 2021; 22(1): 248
  • Salt Transiently Inhibits Mitochondrial Energetics in Mononuclear Phagocytes
    Geisberger S, Bartolomaeus H, Neubert P, Willebrand R, Zasada C, Bartolomaeus T, McParland V, Swinnen D, Geuzens A, Maifeld A, Krampert L, Vogl M, Mähler A, Wilck N, Marko L, Tilic E, Forslund SK, Binger KJ, Stegbauer J, Dechend R, Kleinewietfeld M, Jantsch J, Kempa S, Müller DN
    Circulation 2021; 144: 144-158
  • Small RNA mediated gradual control of lipopolysaccharide biosynthesis affects antibiotic resistance in Helicobacter pylori
    Pernitzsch SR, Alzheimer M, Bremer BU, Robbe-Saule M, de Reuse H, Sharma CM
    Nature Communications 2021; 12(1): 4433
  • Sodium and its manifold impact on our immune system
    Jobin K, Müller DN, Jantsch J, Kurts C
    Trends Immunol 2021; 42(6): 469-479
  • Inflammasomes in dendritic cells: Friend or foe?
    Hatscher L, Amon L, Heger L, Dudziak D
    Immunol Lett 2021; 234: 16-32
  • Global RNA profiles show target selectivity and physiological effects of peptide-delivered antisense antibiotics
    Popella L, Jung J, Popova K, Durica-Mitić S, Barquist L, Vogel J
    Nucleic Acids Res 2021; 49(8): 4705-4724
  • Select hyperactivating NLRP3 ligands enhance the TH1- and TH17-inducing potential of human type 2 conventional dendritic cells
    Hatscher L, Lehmann CHK, Purbojo A, Onderka C, Liang C, Hartmann A, Cesnjevar R, Bruns H, Gross O, Nimmerjahn F, Ivanović-Burmazović I, Kunz M, Heger L, Dudziak D
    Science Signaling 2021; 14(680): eabe1757
  • Evolved to vary: genome and epigenome variation in the human pathogen Helicobacter pylori
    Ailloud F, Estibariz I und Suerbaum S
    FEMS Microbiol Rev 2021; 45(1): fuaa042
  • A Repeat-Associated Small RNA Controls the Major Virulence Factors of Helicobacter pylori.
    Eisenbart SK, Alzheimer M, Pernitzsch SR, Dietrich S, Stahl S, Sharma CM
    Molecular Cell 2020; 80(2): 210-226.e7
  • Human Fcγ-receptor IIb modulates pathogen-specific versus self-reactive antibody responses in lyme arthritis
    Danzer H, Glaesner J, Baerenwaldt A, Reitinger C, Lux A, Heger L, Dudziak D, Harrer T, Gessner A, Nimmerjahn F
    Elife 2020; 9: e55319
  • Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy
    Amon L, Hatscher L, Heger L, Dudziak D, Lehmann CHK
    Pharmaceutics 2020; 12(7): 663
  • Proton Motive Force Disruptors Block Bacterial Competence and Horizontal Gene Transfer.
    Domenech A, Brochado AR, Sender V, Hentrich K, Henriques-Normark B, Typas A and Veening JW
    Cell Host Microbe 2020; 27(4): 544-555.e3
  • A Novel Rapid Sample Preparation Method for MALDI-TOF MS Permits Borrelia burgdorferi Sensu Lato Species and Isolate Differentiation
    Neumann-Cip AC, Fingerle V, Margos G, Straubinger RK, Overzier E, Ulrich S, Wieser A
    Front Microbiol 2020; 11: 690
  • An RNA biology perspective on species-specific programmable RNA antibiotics
    Vogel, Jörg
    Mol Microbiol 2020; 113(3): 550-559
  • A three-dimensional intestinal tissue model reveals factors and small regulatory RNAs important for colonization with Campylobacter jejuni.
    Alzheimer M, Svensson SL, König F, Schweinlin M, Metzger M, Walles H, Sharma CM
    PLoS Pathogens 2020; 16(2): e1008304
  • Precursors for Nonlymphoid-Tissue Treg Cells Reside in Secondary Lymphoid Organs and Are Programmed by the Transcription Factor BATF.
    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
    Immunity 2020; 52(2): 295-312.e11
  • A decade of advances in transposon-insertion sequencing
    Cain AK, Barquist L, Goodman AL, Paulsen IT, Parkhill J
    Nat Rev Genet 2020; 9: 526-540
  • HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting
    Neubert P, Weichselbaum A, Reitinger C, Schatz V, Schröder A, Ferdinand JR, Simon M, Bär AL, Brochhausen C, Gerlach RG, Tomiuk S, Hammer K, Wagner S, van Zandbergen G, Binger KJ, Müller DN, Kitada K, Clatworthy MR, Kurts C, Titze J, Abdullah Z, Jantsch J
    Autophagy 2019; 15(11): 1899-1916
  • Deep learning: new computational modelling techniques for genomics
    Eraslan G, Avsec Ž, Gagneur J, Theis FJ
    Nat Rev Genet 2019; 20(7): 389-403
  • Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
    Menden MP, Wang D, Mason MJ, Szalai B, Bulusu KC, Guan Y, Yu T, Kang J, Jeon M, Wolfinger R, Nguyen T, Zaslavskiy M, AstraZeneca-Sanger Drug Combination DREAM Consortium, Jang IS, Ghazoui Z, Ahsen ME, Vogel R, Neto EC, Norman T, Tang EKY, Garnett MJ, Veroli GYD, Fawell S, Stolovitzky G, Guinney J, Dry JR, Saez-Rodriguez J
    Nat Commun 2019; 10(1): 2674
  • Microbial networks in SPRING – Semi-parametric rank-based correlation and partial correlation estimation for quantitative microbiome data
    Yoon G, Gaynanova I, Müller CL
    Frontiers in Genetics 2019; 10: 516
  • Within-host evolution of Helicobacter pylori shaped by niche-specific adaptation, intragastric migrations and selective sweeps
    Ailloud F, Didelot X, Woltemate S, Pfaffinger G, Overmann, J, Bader RC, Schulz C, Malfertheiner P, Suerbaum S
    Nat Commun 2019; 10(1): 2273
  • Rbpj expression in regulatory T cells is critical for restraining TH2 responses
    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
    Nat Commun 2019; 10(1): 1621
  • Limitation of TCA Cycle Intermediates Represents an Oxygen-Independent Nutritional Antibacterial Effector Mechanism of Macrophages
    Hayek I, Fischer F, Schulze-Luehrmann J, Dettmer K, Sobotta K, Schatz V, Kohl L, Boden K, Lang R, Oefner PJ, Wirtz S, Jantsch J, Lührmann A
    Cell Rep 2019; 26(13): 3502-3510.e6
Associated Institutes

Universität Regensburg

Universitätsklinikum Erlangen