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Recovery of intestinal homeostasis after microbial or immunological challenge

English title Recovery of intestinal homeostasis after microbial or immunological challenge
Applicant Macpherson Andrew
Number 136286
Funding scheme Sinergia
Research institution Institut für klinische Immunologie
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.12.2011 - 30.11.2014
Approved amount 2'000'000.00
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Keywords (7)

colitis; innate mucosal immunity; inflammation restitution; commensal microbial mutualism; infectious enteropathy; innate lymphoid cells; intestinal mononuclear cells

Lay Summary (English)

Lead
Lay summary

Mammals harbor a dense and complex microbial community in their intestines. Under normal conditions, this microbiota lives peacefully within the host. A dense network of interactions (microbes-microbes, microbes-host, host-microbes) affects the composition of the microbiota as well as most aspects of host physiology, especially at the level of the intestinal mucosa. The cellular and molecular mechanisms maintaining mucosal homeostasis are incompletely understood but are of crucial importance to understand the basic biology of the homeostatic interactions, to identify mechanisms allowing host-microbial systems to return to homeostasis upon challenge and to elucidate how disease results when homeostatic mechanisms fail, such as in Crohn’s disease or ulcerative colitis.

In this project we will study mucosal immune responses that restore homeostasis after exposure to microbial or immunological challenge. To do this we will generate axenic (germ-free) and gnotobiotic (defined microbial status) wild type and knockout mouse strains to develop models for transient challenge by commensal (nonpathogenic) bacteria, pathogens (S. Typhimurium), or immune dysregulation. These models will enable systematic study of the mechanisms driving recovery of mucosal homeostasis after challenge. Furthermore, we will analyze the generation, activation and effector functions of key regulatory cells of the mucosal immune system, analyze the role of protective antibodies and of T cell contraction in attenuating intestinal inflammation, and determine the role of mucosal desensitization, in particular, of the intestinal epithelial cells. Lastly, we aim to demonstrate the functional importance of the identified mechanisms for re-establishing mucosal homeostasis in vivo using transgenic and knockout mice, cell depletion strategies, and adoptive cell transfer. The technologies, resources and findings resulting from this work will be of fundamental importance for the field and will define the mechanisms re-establishing mucosal homeostasis after challenge. We speculate that defects in these mechanisms will also be causally involved in the induction and exacerbation of inflammatory bowel disease.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The maternal microbiota drives early postnatal innate immune development
Gomez de Aguero M., Ganal-Vonarburg S. C., Fuhrer T., Rupp S., Uchimura Y., Li H., Steinert A., Heikenwalder M., Hapfelmeier S., Sauer U., McCoy K. D., Macpherson A. J. (2016), The maternal microbiota drives early postnatal innate immune development, in Science, 351(6279), 1296-1302.
Activated group 3 innate lymphoid cells promote T-cell-mediated immune responses
Von Burg N, Chappaz S, Baerenwaldt A, Horvath E, Dasgupta SB, Ashok D, Pieters J, Tacchini-Cottier F, Rolink H, Acha-Orbea H, Finke D (2014), Activated group 3 innate lymphoid cells promote T-cell-mediated immune responses, in PNAS, (35), 12835-12840.
Epithelium-intrinsic NAIP/NLRC4 inflammasome drives expulsion of infected enterocytes to restrict Salmonella replication in the intestinal mucosa
Sellin M.A, Müller A.A, Felmy B, Dolowschiak T, Diard M, Tardivel A, Maslowski K.M, Hardt W.D. (2014), Epithelium-intrinsic NAIP/NLRC4 inflammasome drives expulsion of infected enterocytes to restrict Salmonella replication in the intestinal mucosa, in Cell Host & Microbe, (2), 237.
Interferon-gamma Induces Expression of MHC Class II on Intestinal Epithelial Cells and Protects Mice from Colitis
Thelemann Christoph, Eren Remzi Onur, Coutaz Manuel, Brasseit Jennifer, Bouzourene Hanifa, Rosa Muriel, Duval Anais, Lavanchy Christine, Mack Vanessa, Mueller Christoph, Reith Walter, Acha-Orbea Hans (2014), Interferon-gamma Induces Expression of MHC Class II on Intestinal Epithelial Cells and Protects Mice from Colitis, in PLOS ONE, (1), e86844.
Transcriptional Analysis of Left-sided Colitis, Pancolitis, and Ulcerative Colitis-associated Dysplasia
Bjerrum JT, Nielsen OH, Riis LB, Pittet V, Mueller C, Rogler G, Olsen J (2014), Transcriptional Analysis of Left-sided Colitis, Pancolitis, and Ulcerative Colitis-associated Dysplasia, in Inflamm Bowel Dis, (20(12)), 2340.
TREM-1 Deficiency Can Attenuate Disease Severity without Affecting Pathogen Clearance
Weber Benjamin, Schuster Steffen, Zysset Daniel, Rihs Silvia, Dickgreber Nina, Schurch Christian, Riether Carsten, Siegrist Mark, Schneider Christoph, Pawelski Helga, Gurzeler Ursina, Ziltener Pascal, Genitsch Vera, Tacchini-Cottier Fabienne, Ochsenbein Adrian, Hofstetter Willy, Kopf Manfred, Kaufmann Thomas, Oxenius Annette, Reith Walter, Saurer Leslie, Mueller Christoph (2014), TREM-1 Deficiency Can Attenuate Disease Severity without Affecting Pathogen Clearance, in PLOS PATHOGENS, (1), e1003900.
Antibiotic treatment selects for cooperative virulence of salmonella typhimurium
Diard Médéric, Sellin Mikael E., Dolowschiak Tamas, Arnoldini Markus, Ackermann Martin A., Hardt Wolf Dietrich (2013), Antibiotic treatment selects for cooperative virulence of salmonella typhimurium, in Current Biology, (17), 2000-2005.
'Blooming' in the gut: how dysbiosis might contribute to pathogen evolution
Stecher B, Maier L, Hardt Wolf-Dietrich (2013), 'Blooming' in the gut: how dysbiosis might contribute to pathogen evolution, in Nat Rev Microbiol, 277-284.
Microbiota-driven Hydrogen Fuels Salmonella Typhimurium Invasion of the gut Ecosystem
Maier Lisa, Vyas Rounak, Cordova Carmen Dolores, Lindsay Helen, Schmidt Thomas, Brugiroux Sandrine, Periaswamy Balamurugan, Bauer Rebekka, Sturm Alexander, Schreiber Frank, von Mering Christian, Robinson Mark D, Stecher Bärbel, Hardt Wolf-Dietrich (2013), Microbiota-driven Hydrogen Fuels Salmonella Typhimurium Invasion of the gut Ecosystem, in Cell Host & Microbe, 641-651.
Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment
Kaiser P, Regoes R.R, Dolowschiak T, Wotzka S, Lengefeld J, Slack E, Grant A.J, Ackermann M, Hardt Wolf-Dietrich, Cecum lymph node dendritic cells harbor slow-growing bacteria phenotypically tolerant to antibiotic treatment, in PLoS Biology.
Granulocytes Impose a Tight Bottleneck upon the Gut Luminal Pathogen Population during Salmonella Typhimurium Colitis
Maier L, Diard M, Sellin M.E, Chouffane E.S, Trautwein-Weidner K, Periaswamy B, Slack E, Dolowschiak T, Stecher B, Loverdo C, Regoes R.R, Hardt W.D., Granulocytes Impose a Tight Bottleneck upon the Gut Luminal Pathogen Population during Salmonella Typhimurium Colitis, in PLoS Pathogens.

Collaboration

Group / person Country
Types of collaboration
Prof. Uwe Sauer, ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Novartis Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Christian von Mering, UNIZH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. David Voehringer Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Jörg Stelling, ETH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Bärbel Stecher Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dan Littman United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Martin Ackermann Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Roland Regoes, ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Andrew Macpherson, Wolf-Dietrich Hardt, Daniela Finke, Christoph Müller Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Cell Symposia, Multifaceted Roles of Type 2 Immunity Talk given at a conference Stratification of microbiota in intestine 10.12.2014 Bruges, Belgium, Belgium Macpherson Andrew;
Plenary lecture at the annual meeting of the Chilean Society of Microbiology Talk given at a conference Innate immune responses controlling Salmonella Typhimurium gut infection 03.12.2014 La Serena, Chile Hardt Wolf-Dietrich;
Spring Immunology Symposium, Pontificia Universidad Catolica de Chile Talk given at a conference The importance of phenotypic diversification during Salmonella gut infection 02.12.2014 Santiago, Chile Hardt Wolf-Dietrich;
Pontificia Universidad Catolica de Chile Individual talk Salmonella diarrhea: how a pathogen colonizes the intestine 01.12.2014 Santiago, Chile Hardt Wolf-Dietrich;
University of Würzburg Individual talk Salmonella diarrhea: how the pathogen invades the gut ecosystem 25.11.2014 Würzburg, Germany Hardt Wolf-Dietrich;
TEC-day at the Kantonsschule Limmattal Talk given at a conference Bakterien im Darm: ekelig, nützlich oder egal? 04.11.2014 Zürich, Switzerland Hardt Wolf-Dietrich;
European Mucosal Immunology Group meeting Talk given at a conference Pathogenesis of Salmonellosis: Host cell invasion and epithelium-intrinsic NAIP/NLRC4 inflammasome control mucosal pathogen loads 09.10.2014 Glasgow, Scotland, Great Britain and Northern Ireland Hardt Wolf-Dietrich;
European Mucosal Immunology Meeting Talk given at a conference Host-commensal mutualism in the intestine 09.10.2014 Glasgow, Scotland, Great Britain and Northern Ireland Macpherson Andrew;
DGHM annual meeting Talk given at a conference Restriction of Salmonella replication in the intestinal mucosa by NAIP/NLRC4 inflammasome-driven expulsion on infected enterocytes 05.10.2014 Dresden, Germany Hardt Wolf-Dietrich;
Institute of Medical Microbiology Individual talk Salmonella diarrhea: host innate immune responses limiting the gut infection 18.09.2014 Zürich, Switzerland Hardt Wolf-Dietrich;
Summer School in Immunology Talk given at a conference Mucosal Immunity 08.09.2014 Lausanne, Switzerland Müller Christoph;
HZI summer school Talk given at a conference Salmonella enterica, a common cause of diarrhea; The importance of phenotypic diversification during Salmonella gut infection 22.06.2014 Dresden, Germany Hardt Wolf-Dietrich;
D-BIOL biannual meeting Talk given at a conference Salmonella diarrhea: Native immune defenses protecting the gut epithelium 10.06.2014 Davos, Switzerland Hardt Wolf-Dietrich;
University of Freiburg Individual talk Gut ecosystem invasion by Salmonella typhimurium 19.05.2014 Freiburg, Germany Hardt Wolf-Dietrich;
German-Argentinian Workshop Talk given at a conference The role of intestinal phagocytes in the elicitation of acute Salmonella diarrhea 28.04.2014 Tübingen, Germany Hardt Wolf-Dietrich;
Wolfsberg Immunology PhD Student Meeting Talk given at a conference Chair: Workshops 16.04.2014 Wolfsberg, Switzerland Müller Christoph;
PhD summer school of the Instituto Gulbenkian de Ciencia Talk given at a conference Host and Microbiota interactions 16.04.2014 Portugal, Portugal Hardt Wolf-Dietrich;
Instituto Gulbenkian de Ciencia Individual talk Salmonella diarrhea hinges on the interplay with the microbiota and the host's immune response 16.04.2014 Portugal, Portugal Hardt Wolf-Dietrich;
109th Titisee Conference Talk given at a conference Micobiome-host mutualism 09.04.2014 Titisee, Germany Macpherson Andrew;
Lunteren Conference, NVVI, Dutch Society for Immunology Talk given at a conference Micobiome-host mutualism 03.04.2014 Lunteren, Netherlands Macpherson Andrew;
WIRM/SSAI Meeting Talk given at a conference Workshop - Chair 21.03.2014 Davos, Switzerland Müller Christoph;
Institute Pasteur Individual talk Salmonella diarrhea hinges on a complex interplay with the microbiota and the host's innate immune response 14.03.2014 Paris, France Hardt Wolf-Dietrich;
LS2 Annual Meeting 2014 Talk given at a conference Salmonella diarrhea: how a pathogen invades the host's gut ecosystem 05.02.2014 Lausanne, Switzerland Hardt Wolf-Dietrich;
Medizinisches Forschungszentrum Individual talk Salmonella pathogenicity factors 08.01.2014 Zürich, Switzerland Hardt Wolf-Dietrich;
IUBMB conference Talk given at a conference Host-microbe interactions 16.11.2013 Marrakech, Morocco, Morocco Macpherson Andrew;
EMBO conference on “New Approaches and Concepts in Microbiology Talk given at a conference The antibiotic tolerance problem 14.10.2013 Heidelberg, Germany Hardt Wolf-Dietrich;
Pasteur Institute conference Talk given at a conference Microbe pathogen interactions 07.10.2013 Lille, France, France Macpherson Andrew;
Salmonella Meeting 2013 Talk given at a conference Pathogen host interactions in the streptomycin mouse model of Salmonella diarrhea 05.09.2013 Boston, United States of America Hardt Wolf-Dietrich;
FASEB conference on the Gastrointestinal tract XV: Epithelia, Microbes, Inflammation and Cancer Talk given at a conference Pathogen host interactions in the streptomycin mouse model of Salmonella diarrhea 11.08.2013 Colorado, United States of America Hardt Wolf-Dietrich;
Yale University, Microbiology Graduate Program Seminar Individual talk Pathogen population dynamics reveal key steps of Salmonella infection biology” 02.05.2013 Yale University, New Haven, CT, United States of America Hardt Wolf-Dietrich;
Keystone Symposia on Molecular and Cellular Biology Talk given at a conference IgA Against Commensal Intestinal Microbes – Induction and Function 10.02.2013 Colorado, USA, United States of America Macpherson Andrew;


Self-organised

Title Date Place
Sinergia Retreat-Year 3 14.12.2014 DKF, Unibern, Bern, Switzerland
10th Sinergia Meeting 20.10.2014 Unibas, Basel, Switzerland
9th Sinergia Meeting 29.04.2014 ETHZ, Zürich, Switzerland
Sinergia Retreat-Year 2 20.01.2014 Bern, Switzerland
7th Sinergia Meeting 04.11.2013 Unibas, Basel, Switzerland
6th Sinergia Meeting 26.08.2013 ETH, Zürich, Switzerland
5th Sinergia Meeting 10.07.2013 DKF, Unibe, Bern, Switzerland
Sinergia Retreat-Year 1 07.03.2013 Gerschnalp, Engelberg, Switzerland
3rd Sinergia Meeting 05.11.2012 University of Bern, Switzerland
2nd Sinergia Meeting 09.07.2012 ETH Zürich, Switzerland
1st Sinergia Meeting 20.02.2012 University of Bern, Switzerland

Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Bacteria in your mom’s gut may have influenced the way you fight off infections today QUARTZ International 2016
Media relations: print media, online media Bébés renforcés grâce aux microbes de leur mère 20 minutes Rhaeto-Romanic Switzerland 2016
Media relations: print media, online media Mother’s Microbiome Shapes Offspring’s Immunity The Scientist International 2016
Media relations: print media, online media Mütterliche Starthilfe fürs Immunsystem Spektrum International 2016
Media relations: print media, online media Angeborene lymphoide Zellen lösen Abwehrreaktion von T-Zellen aus Uni Research German-speaking Switzerland 2014
Media relations: print media, online media Die Leber – ein effizienter Filter, der uns vor der Invasion durch ungebetene Darmbakterien schützt German-speaking Switzerland 2014
Media relations: print media, online media Geräuschloses Begräbnis: Wie Fresszellen beim Zellsterben für Ordnung sorgen NZZ German-speaking Switzerland 2014
Media relations: print media, online media Good bacteria in the intestine prevent diabetes International 2014
Talks/events/exhibitions Information Session for Bernese Politicians German-speaking Switzerland 2014

Awards

Title Year
Pfizer Research Prize in Immunology 2017
Swiss Society for Gastroenterology 2016
Goldene Eule; best academic teacher award, D-BIOL, ETH Zürich, 2013 2013
Membership of Swiss Academy of Medical Sciences 2013

Associated projects

Number Title Start Funding scheme
145006 Apparatus for Colonoscopy and Endoscopic Manipulations in Mice 01.09.2013 R'EQUIP
170084 Intestinal tissue resident memory T cells in inflammation and homeostasis 01.11.2016 Project funding (Div. I-III)
138392 Pathophysiology of intestinal intraepithelial lymphocytes: Functional heterogeneity and plasticity of CD8aa TCRab T cells 01.11.2011 Project funding (Div. I-III)
140700 Compartmentalisation of commensal intestinal microbes and host IgA immunity in maintaining host-microbial mutualism 01.04.2012 Project funding (Div. I-III)
153247 Development and immune function of innate lymphoid cells 01.05.2014 Project funding (Div. I-III)
145016 Bringing flow cytometry a step further: expanding biomedical research capabilities with an imaging flow cytometer 01.10.2012 R'EQUIP

Abstract

Mammals harbor a dense and complex microbial community in their intestines. Under homeostasis, this microbiota lives mutualistically within the host. A dense network of interactions (microbes-microbes, microbes-host, host-microbes) affects the composition of the microbiota as well as most aspects of host physiology producing homeostasis, especially at the level of the intestinal mucosa. The cellular and molecular mechanisms maintaining mucosal homeostasis are incompletely understood. Nonetheless, they are of crucial importance to understand the basic biology of the homeostatic interactions, to identify mechanisms allowing host-microbial systems to return to homeostasis upon challenge and to elucidate how disease results when homeostatic mechanisms fail, such as in Crohn’s disease or ulcerative colitis.Analysis of the mechanisms maintaining mucosal homeostasis has been hampered by our incomplete understanding of the cellular mechanisms of the intestinal immune system and by the sheer complexity of this biology. The “microbiota” is composed of 500-1500 microbial species, most of which have not been analyzed. Thus, key stimuli affecting mucosal homeostasis remain poorly defined. Model systems with reduced complexity are therefore of great importance.We propose to develop axenic mouse models (totally lacking microbes) and gnotobiotic mice associated with a defined gut flora composed of eight isolated strains of the altered Schädler flora (ASF mice) to study mucosal immune responses that restore homeostasis after exposure to microbial or immunological challenge. This will be achieved by:1.Generation of axenic and ASF-associated wild type and knockout mice.2.Use of axenic and ASF-mice to develop models for transient challenge by commensals (HA107), pathogens (S. Typhimurium), or immune dysregulation. These models will enable systematic study of the mechanisms driving recovery of mucosal homeostasis after challenge3.Analyze the generation, activation and effector functions of key regulatory cells of the mucosal immune system, including innate lymphoid cells (LTi, NKR LTi, NK, nuocytes), regulatory T-cells and intestinal mononuclear phagocytes (CX3CR1hi/lo macrophages, CD103+CD11b+/- dendritic cells, CD11c+E-cadherin+ phagocytes).4.Analyze the role of protective antibodies and of T cell contraction in attenuating intestinal inflammation.5.Analyze the role of mucosal desensitization, in particular, of the intestinal epithelial cells6.Demonstrate the functional importance of the identified mechanisms for re-establishing mucosal homeostasis in vivo using transgenic and knockout mice, cell depletion strategies, adoptive cell transfer.This project can only be tackled by the collaborative added value, specialized resources and infrastructure of the four synergistic laboratories: i.e. A. Macpherson, a world-leader in mucosal immunology who has established a unique facility for generating and handling axenic and gnotobiotic mice; ii. C. Mueller, an international expert in mouse IBD models and the studies of Treg- and intestinal mononuclear cell function; iii. D. Finke, an international expert in the development and function of LTi cells; and iv. W.-D. Hardt, an international expert in gut infection models for Salmonella enteropathy. The technologies, resources and findings resulting from this work will be of fundamental importance for the field and will define the mechanisms re-establishing mucosal homeostasis after challenge. We speculate that defects in these mechanisms will also be causally involved in the induction and exacerbation of inflammatory bowel disease.
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