Project

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Molecular dissection of microbe-induced immunopathlogy

English title Molecular dissection of microbe-induced immunopathlogy
Applicant Krebs Philippe
Number 138188
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pathologie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.09.2012 - 31.12.2015
Approved amount 377'366.00
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All Disciplines (5)

Discipline
Immunology, Immunopathology
Biochemistry
Genetics
Experimental Cancer Research
Molecular Biology

Keywords (7)

Immunopathology; Myeloproliferative disease; Inflammation; Inflammatory bowel disease; Cancer; Genetic mutations; Microbes

Lay Summary (English)

Lead
Lay summary

Chronic inflammation of microbial etiology has been suggested as the underlying cause of several debilitating conditions, particularly in patients afflicted with inflammatory bowel disease (IBD) or certain forms of malignancies. In this project, we will work along the central hypothesis that microbes, including commensals, represent a major cause for inflammation-induced immunopathology in genetically susceptible individuals. To address this issue, we will use two distinct mouse mutants with defined genetic alterations affecting the hematopoietic and the radio-resistant compartment, respectively. In particular, we aim to provide a detailed analysis of the molecular and cellular processes involved in microbe-associated pathogenesis in a model of myeloproliferative disorder and a model of IBD. We anticipate that the planned investigations will not only extend our current knowledge on the role of microorganisms as trigger of inflammatory disorders and cancer; they may also help to develop treatment strategies with potential translation into the clinic or to define new genetic markers of disease susceptibility, thereby allowing targeted preventive care.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer
Pastille Eva, Wasmer Marie-Hélène, Adamczyk Alexandra, Vu Vivian P., Mager Lukas F., Phuong Nhi Ngo Thi, Palmieri Vittoria, Simillion Cedric, Hansen Wiebke, Kasper Stefan, Schuler Martin, Muggli Beat, McCoy Kathy D., Buer Jan, Zlobec Inti, Westendorf Astrid M., Krebs Philippe (2019), The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer, in Mucosal Immunology, 1-14.
Non‐apoptotic TRAIL function modulates NK cell activity during viral infection
Alves Ludmila Cardoso, Berger Michael D, Koutsandreas Thodoris, Kirschke Nick, Lauer Christoph, Spörri Roman, Chatziioannou Aristotelis, Corazza Nadia, Krebs Philippe (2019), Non‐apoptotic TRAIL function modulates NK cell activity during viral infection, in EMBO reports, e48789.
The ESRP1-GPR137 axis contributes to intestinal pathogenesis
Mager Lukas Franz, Koelzer Viktor Hendrik, Stuber Regula, Thoo Lester, Keller Irene, Koeck Ivonne, Langenegger Maya, Simillion Cedric, Pfister Simona P, Faderl Martin, Genitsch Vera, Tcymbarevich Irina, Juillerat Pascal, Li Xiaohong, Xia Yu, Karamitopoulou Eva, Lyck Ruth, Zlobec Inti, Hapfelmeier Siegfried, Bruggmann Rémy, McCoy Kathy D, Macpherson Andrew J, Müller Christoph, Beutler Bruce, et al. (2017), The ESRP1-GPR137 axis contributes to intestinal pathogenesis, in eLife, 6, 1.
The Role of IL-33-Dependent Inflammation in the Tumor Microenvironment
Wasmer Marie-Hélène, Krebs Philippe (2017), The Role of IL-33-Dependent Inflammation in the Tumor Microenvironment, in Front. Immunol., 7(-), 1-13.
Cytokine-Induced Modulation of Colorectal Cancer
Mager Lukas F., Wasmer Marie-Hélène, Rau Tilman T., Krebs Philippe (2016), Cytokine-Induced Modulation of Colorectal Cancer, in Frontiers in Oncology, 6, 1/96-18.
The IL-33/ST2 pathway contributes to intestinal tumorigenesis in humans and mice
Kirsten D. Mertz, Lukas F. Mager, Marie-Hélène Wasmer, Philippe Krebs (2015), The IL-33/ST2 pathway contributes to intestinal tumorigenesis in humans and mice, in OncoImmunology, 5(1), 1-11.
Slc15a4, a Gene Required for pDC Sensing of TLR Ligands, Is Required to Control Persistent Viral Infection
Blasius Amanda L., Krebs Philippe, Sullivan Brian M, Oldstone Michael B, Popkin Daniel L. (2012), Slc15a4, a Gene Required for pDC Sensing of TLR Ligands, Is Required to Control Persistent Viral Infection, in PLOS Pathog, 8 (9), 1002915.
IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms
Mager Lukas, Riether Carsten, Schürch Christian, Banz Yara, Wasmer Marie-Hélène, Stuber Regula, Theocharides Alexandre, Li Xiaohong, Xia Yu, Hirohisa Saito, Nakae Susumu, Baerlocher Gabriela, Manz Markus, McCoy Kathy, Macpherson Andrew, Ochsenbein Adrian, Beutler Bruce, Krebs Philippe, IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms, in The Journal of Clinical Investigation.

Collaboration

Group / person Country
Types of collaboration
Prof. Bruce Beutler, The Scripps Research Institute United States of America (North America)
- Publication
Prof. Andrew Macpherson and Dr Kathy McCoy, University of Bern Switzerland (Europe)
- Publication
Tobias Junt, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Adrian Ochsenbein, University of Bern, Switzerland Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Christoph Mueller, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Markus Manz, Dr. Alexandre Theocharides, USZ, Zurich, Switzerland Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Kirsten D. Mertz / aInstitute of Pathology, Cantonal Hospital Baselland, Liestal, Switzerland Switzerland (Europe)
- Publication
Dr. Ben Croker, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Seminar Talk given at a conference mRNA splicing and epithelial integrity 17.12.2015 Bern, Switzerland Krebs Philippe;
TOLL 2015 meeting Poster IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms 30.09.2015 Marbella, Spain Krebs Philippe;
Meeting Talk given at a conference SLC15A4 - a link between lysosomal transport and innate immune receptor function 11.08.2015 Lugano, Switzerland Krebs Philippe;
Seminar Talk given at a conference Cytokines and regulation of myeloproliferative neoplasms 14.04.2015 Basel, Switzerland Krebs Philippe;
Seminar Talk given at a conference Inflammation, microbes and cancer - models immunopathology 23.02.2015 Bern, Switzerland Krebs Philippe;
Internal Seminar Talk given at a conference Slc15a4 - a link between lysosomal transport and innate immune receptor function 09.12.2014 Basel, Switzerland Krebs Philippe;
Seminar Talk given at a conference Control of adaptive immunity by pDC and NK cells 27.11.2014 Bern, Switzerland Krebs Philippe;
Weiter-und Fortbildungsseminar Talk given at a conference Cytokines and regulation of myeloproliferative neoplasms 06.11.2014 Zürich, Switzerland Krebs Philippe;
Visit / Seminar Talk given at a conference Innate immunity as a double edged sword: collateral damages mediated by inflammation 04.08.2014 Essen, Germany Krebs Philippe;
Reunion Exp. Imm. Talk given at a conference Cytokines and regulation of myeloproliferative neoplasms 12.06.2014 Zürich, Switzerland Krebs Philippe;
CHUV Individual talk Cross-talk of innate and adaptive immunity in sterile and infectious conditions 13.02.2013 check, Switzerland Krebs Philippe;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media https://www.unibe.ch/news/media_news/media_relations_e/media_releases/2019/medienmitteilungen_2019/a Media release UniBE International 2019
Media relations: print media, online media Berner bremsen Blutkrankheit Basellandschaftliche Zeitung German-speaking Switzerland 2015
Media relations: print media, online media Berner bremsen Blutkrankheiten Argauer Zeitung German-speaking Switzerland 2015
Media relations: print media, online media Berner Krebsforschende bremsen tödliche Blutkrankheiten MyScience.ch International German-speaking Switzerland 2015
Media relations: print media, online media Forscher bremsen tödliche Blutkrankheit St Galler Tagblatt German-speaking Switzerland 2015
Media relations: print media, online media http://www.unibe.ch/aktuell/medien/media_relations/medienmitteilungen/2015/medienmitteilungen_2015/b UniBE Medienmitteilung International German-speaking Switzerland 2015
Media relations: print media, online media MPN: Botenstoff-Blockade verhindert Andocken DocCheck News International German-speaking Switzerland 2015
Media relations: print media, online media Neuer Ansatz gegen MPN Newsroom.interpharma.ch International German-speaking Switzerland 2015

Awards

Title Year
Award from the Bern Immunology Club: "BIC prize – best paper – 2015" (Mager et al., JCI, 2015) 2016
Dr. Lutz Zwillenberg-Preis to Lukas Mager for his thesis «Molecular Dissection of Inflammation-induced Immunopathologies» 2016
Boehringer Ingelheim Fonds PhD fellowship to Lukas Mager, MD, for his project “Molecular dissection of microbe-induced immunopathology”. Fellowship of 30 months. 2012

Associated projects

Number Title Start Funding scheme
145006 Apparatus for Colonoscopy and Endoscopic Manipulations in Mice 01.09.2013 R'EQUIP
121410 A forward genetic approach to uncover novel molecules required for NK cell function and CD8+ T cell priming 01.10.2008 Fellowships for advanced researchers
121410 A forward genetic approach to uncover novel molecules required for NK cell function and CD8+ T cell priming 01.10.2008 Fellowships for advanced researchers
163086 mRNA splicing and epithelial integrity 01.04.2016 Project funding (special)

Abstract

MOLECULAR DISSECTION OF MICROBE-INDUCED IMMUNOPATHLOGYBackground and rationale: Innate and adaptive immunity are complementary systems indispensable for the survival of higher metazoans against infections. Recognition of foreign (or “danger”) molecules is a critical step to initiate an inflammatory reaction leading to the induction of defense mechanisms. Yet immuno-regulation is not of lesser importance, as it prevents exacerbated inflammation that may result in chronic inflammation and detrimental immunopathology. Genetic mutations or polymorphisms shape the extent of an inflammatory response. Therefore, both the genetic susceptibility of a host and the virulence of the invading pathogen(s) will determine the outcome of an inflammatory reaction. Chronic inflammation of microbial etiology has been suggested as the underlying cause of several debilitating conditions, particularly in patients afflicted with inflammatory bowel disease (IBD) or certain forms of malignancies. Gastric cancer has been associated with Helicobacter pylori infection, cervical cancer with human papilloma virus and hepatocellular carcinoma with hepatitis virus B and C, for instance. It is therefore essential to determine the parameters modulating host / microbes interactions in such disorders.Working hypothesis: In this project, we will work along the central hypothesis that microbes, including commensals, represent a major cause for inflammation-induced immunopathology in genetically susceptible individuals. To address this issue, we will use two distinct, recently identified mouse mutants with defined genetic alterations affecting the hematopoietic and the radio-resistant compartment, respectively. Specific aims: The major aim of this research project is to provide a detailed analysis of the molecular and cellular processes involved in microbe-associated pathogenesis in a model of myeloproliferative disorder and a model of IBD. Both are characterized by inflammatory conditions elicited by microbes and both may serve as models for microbe-triggered neoplasia.Specifically, we will investigate the ways cross-talk between Toll-like receptor (TLR) signaling and the phosphoinositide pathway using an unbiased genetic approach. We will also mechanistically evaluate how disruption of distinct central components of TLR signaling can counteract fatal myeloproliferative disease and whether commensals may instigate this disorder in mice deficient in the inositol phosphatase SHIP1.Furthermore, we will elucidate the role of a mutated allele of Esrp1, an epithelium-specific splicing regulator, for the development of IBD, and potentially colorectal cancer.Expected significance: The intended studies will use two novel mouse mutants to dissect key factors that may modulate hyperproliferation of myeloid cells and/or contribute to immunopathology exacerbated by chronic inflammatory conditions. We anticipate that the planned investigations will not only extend our current knowledge on the role of microorganisms as trigger of inflammatory disorders and cancer; they may also help to develop treatment strategies with potential translation into the clinic or to define new genetic markers of disease susceptibility, thereby allowing targeted preventive care.
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