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Exploiting the immunomodulatory properties of Helicobacter pylori for the treatment of immunological disorders

English title Exploiting the immunomodulatory properties of Helicobacter pylori for the treatment of immunological disorders
Applicant Müller Anne
Number 157841
Funding scheme Temporary Backup Schemes
Research institution Institut für Molekulare Krebsforschung Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Immunology, Immunopathology
Start/End 01.04.2015 - 31.03.2020
Approved amount 1'992'150.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Experimental Microbiology

Keywords (7)

microflora and immunomodulation; asthma and allergy prevention; dendritic cell subsets; immune tolerance; bacterial immunomodulators; models of allergy and inflammatory disorders; inflammasome activation

Lay Summary (German)

Lead
Helicobacter pylori besiedelt den Magen des Menschen seit über 60'000 Jahren und gilt somit als Bestandteil des normalen menschlichen Mikrobioms. In ca. 10-20% aller Infizierten löst die chronische Besiedelung mit H. pylori Magenerkrankungen aus, die von chronischer Magenschleimhautentzündung bis zu Magengeschwüren und sogar Krebs reichen können. In asymptomatischen Trägern hingegen scheint H. pylori einen Schutz vor Allergien und Entzündungskrankheiten zu bewirken. Die Mechanismen, die dieser Schutzfunktion zugrundeliegen, sollen im Rahmen des vorliegenden Projekts untersucht und letztlich zu Präventions- und therapeutischen Zwecken ausgenutzt werden.
Lay summary
H. pylori hat im Lauf seiner Ko-Evolution mit dem Menschen immunmodulatorische Eigenschaften erworben, die es dem Keim erlauben, eine chronische Infektion zu etablieren. Zur "Toleranz" von H. pylori durch den Wirt trägt einerseits der Zeitpunkt der Erstinfektion bei, die in der Regel im jungen Kindesalter stattfindet, und andererseits die effiziente "Umpolarisierung" und Modulation der Immunantwort durch den Keim selbst. Das frühkindliche Immunsystem ist noch unreif und in den ersten Lebenswochen und -monaten darauf ausgerichtet, Toleranz gegenüber dem normalen Mikrobiom und gegenüber Nahrungsmitteln aufzubauen. Diese Toleranz erstreckt sich bei frühkindlicher Erstinfektion auch auf H. pylori, der unter diesen Umständen nicht als Krankheitserreger wahrgenommen, sondern als Teil des normalen Mikrobioms toleriert wird. Zusätzlich hat H. pylori sogenannte Immunmodulatoren entwickelt, die vom Keim sekretiert werden und gezielt Zellen des Immunsystems angreifen. Ein epidemiologisch messbarer Nebeneffekt der Toleranz von/durch H. pylori ist die gleichzeitige Unterdrückung von Immunantworten gegen Allergene. H. pylori-infizierte Träger, insbesondere Kinder, weisen ein geringeres Allergie- und Asthmarisiko auf als der Rest der jeweils untersuchten Population. Wir konnten im Tiermodell den Schutz vor Allergien, insbesondere allergischem Asthma, durch H. pylori nachvollziehen. Im vorliegenden Projekt möchten wir dieses Tiermodell weiter ausnutzen um die Toleranz-fördernden Eigenschaften von H. pylori mechanistisch aufzuklären. Insbesondere interessiert uns, wie die bereits identifizierten H. pylori Immunmodulatoren wirken, welche Zellen sie angreifen und wie sie diese Zellen im Sinn des Keims manipulieren. Von den Experimenten erhoffen wir uns Aufschluss über die immunmodulatorischen Eigenschaften von H. pylori und planen, diese dann im Sinne der besseren Prävention und Behandlung von Allergikern und Asthmatikern in wirksame Interventionsstrategien zu übesetzen.
Direct link to Lay Summary Last update: 09.03.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Molecular Pathogenesis and Signal Transduction by Helicobacter pylori
Nicole Tegtmeyer, Steffen Backert (2017), Molecular Pathogenesis and Signal Transduction by Helicobacter pylori, Springer, Schweiz.
Inflammasome Signaling and Bacterial Infections
Steffen Backert (2016), Inflammasome Signaling and Bacterial Infections, Springer, Schweiz.
Lymphotoxin β receptor signalling executes Helicobacter pylori-driven gastric inflammation in a T4SS-dependent manner.
Mejías-Luque Raquel, Zöller Jessica, Anderl Florian, Loew-Gil Elena, Vieth Michael, Adler Thure, Engler Daniela B, Urban Sabine, Browning Jeffrey L, Müller Anne, Gerhard Markus, Heikenwalder Mathias (2016), Lymphotoxin β receptor signalling executes Helicobacter pylori-driven gastric inflammation in a T4SS-dependent manner., in Gut, 1-13.
Microbes and asthma: Opportunities for intervention.
Smits Hermelijn H, Hiemstra Pieter S, Prazeres da Costa Clarissa, Ege Markus, Edwards Michael, Garn Holger, Howarth Peter H, Jartti Tuomas, de Jong Esther C, Maizels Rick M, Marsland Ben J, McSorley Henry J, Müller Anne, Pfefferle Petra I, Savelkoul Huub, Schwarze Jürgen, Unger Wendy W J, von Mutius Erika, Yazdanbakhsh Maria, Taube Christian (2016), Microbes and asthma: Opportunities for intervention., in The Journal of allergy and clinical immunology, 137(3), 690-7.
The Gastrointestinal Tract Microbiota and Allergic Diseases.
Kyburz Andreas, Müller Anne (2016), The Gastrointestinal Tract Microbiota and Allergic Diseases., in Digestive diseases (Basel, Switzerland), 34(3), 230-43.
The Immunomodulator VacA Promotes Immune Tolerance and Persistent Helicobacter pylori Infection through Its Activities on T-Cells and Antigen-Presenting Cells.
Djekic Aleksandra, Müller Anne (2016), The Immunomodulator VacA Promotes Immune Tolerance and Persistent Helicobacter pylori Infection through Its Activities on T-Cells and Antigen-Presenting Cells., in Toxins, 8(6), 1-10.
H. pylori-Induced DNA Strand Breaks Are Introduced by Nucleotide Excision Repair Endonucleases and Promote NF-κB Target Gene Expression.
Hartung Mara L, Gruber Dorothea C, Koch Katrin N, Grüter Livia, Rehrauer Hubert, Tegtmeyer Nicole, Backert Steffen, Müller Anne (2015), H. pylori-Induced DNA Strand Breaks Are Introduced by Nucleotide Excision Repair Endonucleases and Promote NF-κB Target Gene Expression., in Cell reports, 13(1), 70-9.
Helicobacter pylori activates the TLR2/NLRP3/caspase-1/IL-18 axis to induce regulatory T-cells, establish persistent infection and promote tolerance to allergens.
Koch Katrin N, Müller Anne (2015), Helicobacter pylori activates the TLR2/NLRP3/caspase-1/IL-18 axis to induce regulatory T-cells, establish persistent infection and promote tolerance to allergens., in Gut microbes, 6(6), 382-7.
Helicobacter pylori-specific protection against inflammatory bowel disease requires the NLRP3 inflammasome and IL-18.
Engler Daniela B, Leonardi Irina, Hartung Mara L, Kyburz Andreas, Spath Sabine, Becher Burkhard, Rogler Gerhard, Müller Anne (2015), Helicobacter pylori-specific protection against inflammatory bowel disease requires the NLRP3 inflammasome and IL-18., in Inflammatory bowel diseases, 21(4), 854-61.
Helicobacter urease-induced activation of the TLR2/NLRP3/IL-18 axis protects against asthma.
Koch Katrin N, Hartung Mara L, Urban Sabine, Kyburz Andreas, Bahlmann Anna S, Lind Judith, Backert Steffen, Taube Christian, Müller Anne (2015), Helicobacter urease-induced activation of the TLR2/NLRP3/IL-18 axis protects against asthma., in The Journal of clinical investigation, 125(8), 3297-302.

Collaboration

Group / person Country
Types of collaboration
NYU Medical Center United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Dept Biochemie, Uni Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Vanderbilt Univ United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Uniklinik Essen Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Universität Erlangen Lehrstuhl Mikrobiologie Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Leiden University Medical Center Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
UZH Gastroenterologie Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
11th World Immune regulation meeting (WIRM), Talk given at a conference Eosinophils have regulatory properties in bacterial infection 21.03.2017 Davos, Switzerland Arnold Isabelle;
European Midwinter Immunology meeting, St. Johann, Austria. Talk given at a conference Division of labor among myeloid cells during H. pylori infections 16.01.2017 St Johann, Austria Müller Anne;
British Society for Immunology (BSI) annual congress, Talk given at a conference Myeloid cells in Helicobacter infections 14.12.2016 Liverpool, Great Britain and Northern Ireland Arnold Isabelle;
Symposium on Infection, Inflammation and Cancer, Liestal, Switzerland. Talk given at a conference Helicobacter pylori: pathogen or symbiont? 22.11.2016 Liestal, Switzerland Müller Anne;
University of Basel, Pharmazentrum. Seminarreihe Individual talk Helicobacter pylori in health and disease 12.11.2016 Basel, Switzerland Müller Anne;
29th International meeting of the European Helicobacter and microbiota study group, Magdeburg, Germany. Talk given at a conference The gut microbiota and allergic diseases. 16.09.2016 Magdeburg, Germany Müller Anne;
12th International Conference on Pathogenesis and Host response in Helicobacter infections, Lo-skolen, Helsingor, Denmark. Talk given at a conference Helicobacter and extragastric diseases 13.07.2016 Helsingör, Denmark Müller Anne;
12th Workshop on Host Response in Helicobacter Infections, Talk given at a conference Myeloid cells in Helicobacter infection 13.07.2016 Helsingör, Denmark Arnold Isabelle;
Helmholtz-Zentrum für Infektion, Braunschweig, Germany. Seminarreihe Individual talk Helicobacter pylori in health and disease 18.05.2016 Braunschweig, Germany Müller Anne;
Swiss Society for Immunology, Montreux, Switzerland. Talk given at a conference Post-transcriptional and epigenetic regulation of diffuse large B-cell lymphomagenesis 29.04.2016 Montreux, Switzerland Müller Anne;
Infectious Disease Immunology meets Molecular Microbiology, Erlangen, Germany. Talk given at a conference Immunomodulatory activity of H. pylori on dendritic cells and T-cells. 25.04.2016 Erlangen, Germany Müller Anne;
Karolinska-Institutet, Stockholm, Sweden. Seminarreihe Individual talk Helicobacter pylori in health and disease 12.04.2016 Stockholm, Sweden Müller Anne;
10th World Immune regulation meeting (WIRM), Talk given at a conference Myeloid cells in Helicobacter infection 23.03.2016 Davos, Switzerland Arnold Isabelle;
University of Heidelberg, Dept. of Microbiology and Immunology Seminarreihe Individual talk Helicobacter pylori in health and disease 11.01.2016 Heidelberg, Germany Müller Anne;
Seminarreihe Individual talk Immunomodulatory activity of H. pylori on dendritic cells and T-cells 24.11.2015 Leiden, Netherlands Müller Anne;
Helicobacter workshop, German Society for Hygiene and Microbiology Talk given at a conference Immunomodulatory activity of H. pylori on dendritic cells and T-cells 19.11.2015 Herrsching, Germany Müller Anne;
ETOX meeting, Braga, Portugal. Talk given at a conference Helicobacter pylori in health and disease 11.09.2015 Braga, Portugal Müller Anne;
Medizinische Hochschule Hannover, Germany Individual talk Helicobacter pylori in health and disease 15.07.2015 Hannover, Germany Müller Anne;
Japanese Gastroenterology Conference, Sendai, Japan. Talk given at a conference Helicobacter pylori in health and disease 01.05.2015 Sendai, Japan Müller Anne;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Clinical Research Day, University Hospital Zurich Talk 09.02.2017 Zürich, Switzerland Müller Anne;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Dieser Keim macht nicht nur krank FAZ International 2016

Awards

Title Year
Best workshop oral presentation prize, 11th World Immune regulation meeting (WIRM), Davos, Switzerland 2017

Associated projects

Number Title Start Funding scheme
143609 The two faces of Helicobacter pylori: unraveling the virulence and tolerance determinants governing persistence, immune tolerance, and pathogenicity 01.11.2012 Project funding (Div. I-III)

Abstract

The gram-negative bacterial pathogen Helicobacter pylori is predominantly known for its tight association with peptic ulcer disease and gastric cancer. However, recent epidemiological evidence suggests that chronic infection with H. pylori may at the same time be beneficial to the host by conferring protection against asthma, other allergic disease manifestations and inflammatory bowel diseases (IBD). We have recently provided the first definitive experimental evidence showing that allergen-induced asthma fails to develop in H. pylori-infected mice. The protective effects are particularly evident in mice infected at an early age, and depend on the H. pylori-mediated induction of regulatory T-cells (Tregs) with highly suppressive activity. H. pylori infection efficiently reprograms dendritic cells in the stomach-draining lymph nodes towards a tolerance-promoting phenotype; the “tolerogenic” activity of H. pylori-experienced DCs requires DC-intrinsic inflammasome activation and secretion of interleukin-18. Interestingly, active tolerization with H. pylori extract is as efficient as live infection in preventing asthma. Within this grant, we will first explore the mechanistic basis of H. pylori-induced immune tolerance and will then exploit the immunomodulatory properties of the bacteria for the development of innovative new asthma and allergy prevention and treatment strategies.
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