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Compartmentalisation of commensal intestinal microbes and host IgA immunity in maintaining host-microbial mutualism

English title Compartmentalisation of commensal intestinal microbes and host IgA immunity in maintaining host-microbial mutualism
Applicant Macpherson Andrew
Number 140700
Funding scheme Project funding (Div. I-III)
Research institution Universität Bern
Institution of higher education University of Berne - BE
Main discipline Immunology, Immunopathology
Start/End 01.04.2012 - 31.03.2015
Approved amount 782'000.00
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Keywords (4)

intestine; IgA; commensal bacteria; B lymphocytes

Lay Summary (English)

Lead
Lay summary

Healthy humans and other animals have enormous numbers of bacteria and other microorganisms in the lower intestine. These are very good for us as they help us harvest energy from food, provide us with vitamins, break down toxic chemicals and prevent pathogenic bacteria from causing disease. For health, these commensal microbes must be contained inside the intestinal tube, but allowed to flourish. In this project we will study the way in which the main antibody of the body, IgA, is secreted into the intestine to promote the peaceful coexistence of intestinal commensal bacteria and the host. We will focus on how live microbes are prevented from entering the tissues of the body, yet provided with the right environment next to the intestinal membrane to form stable growing communities.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Penetrability of the inner mucus layer: who is out there?
Li Hai, Limenitakis Julien P, Ganal Stephanie C, Macpherson Andrew J (2015), Penetrability of the inner mucus layer: who is out there?, in EMBO reports, 16, 127-129.
The outer mucus layer hosts a distinct intestinal microbial niche
Li Hai, Limenitakis Julien P, Fuhrer Tobias, Geuking Markus B, Lawson Melissa A, Wyss Madeleine, Brugiroux Sandrine, Keller Irene, Macpherson Jamie A, Rupp Sandra, Stolp Bettina, Stein Jens V, Stecher Bärbel, Sauer Uwe, McCoy Kathy D, Macpherson Andrew J (2015), The outer mucus layer hosts a distinct intestinal microbial niche, in Nature Communications, 6, 1-13.
Microbiota-Derived Compounds Drive Steady-State Granulopoiesis via MyD88/TICAM Signaling
Balmer Maria L., Schuerch Christian M., Saito Yasuyuki, Geuking Markus B., Li Hai, Cuenca Miguelangel, Kovtonyuk Larisa V., Mccoy Kathy D., Hapfemeier Siegfried, Ochsenbein Adrian F., Manz Markus G., Sack Emma, Macpherson Andrew J. (2014), Microbiota-Derived Compounds Drive Steady-State Granulopoiesis via MyD88/TICAM Signaling, in JOURNAL OF IMMUNOLOGY, 193(10), 5273-5283.
The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota.
Balmer Maria L, Slack Emma, de Gottardi Andrea, Lawson Melissa A E, Hapfelmeier Siegfried, Miele Luca, Grieco Antonio, Van Vlierberghe Hans, Fahrner René, Patuto Nicola, Bernsmeier Christine, Ronchi Francesca, Wyss Madeleine, Stroka Deborah, Dickgreber Nina, Heim Markus H, McCoy Kathy D, Macpherson Andrew J (2014), The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota., in Science translational medicine, 6(237), 237-66.

Collaboration

Group / person Country
Types of collaboration
Prof. Uwe Sauer Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof Kathy McCoy Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
The Abelson Symposium Talk given at a conference The Outside-In Perspective on Host-Microbial Immune Interactions 08.06.2015 Washington, United States of America Macpherson Andrew;
Keystone Symposia, Gut Microbiota Modulation of Host Physiology: The Search for Mechanism Talk given at a conference Stratification of Intestinal Microbes 01.03.2015 Keystone, Colorado, United States of America Macpherson Andrew;
Cell Symposia: Multifaceted Roles of Type 2 Immunity Talk given at a conference Stratification of microbiota in intestine 10.12.2014 Bruges, Belgium Macpherson Andrew;
European Mucosal Immunology Meeting Talk given at a conference Host-commensal mutualism in the intestine 09.10.2014 Glasgow, Great Britain and Northern Ireland Macpherson Andrew;
Lunteren Conference, NVVI, Dutch Society for Immunology Talk given at a conference Host-microbe interactions 28.04.2014 Lunteren, Netherlands Macpherson Andrew;
109th Titisee Conference Talk given at a conference Microbiome-host mutualism 14.04.2014 Titisee, Germany Macpherson Andrew;
IUBMB conference Talk given at a conference Host-microbe interactions 15.11.2013 Marrakech, Morocco Macpherson Andrew;
Pasteur Institute conference Talk given at a conference Microbe pathogen interactions 22.10.2013 Lille, France Macpherson Andrew;
Keystone Symposia on Molecular and Cellular Biology Talk given at a conference IgA Against Commensal Intestinal Microbes – Induction and Function 08.02.2013 Colorado, United States of America Macpherson Andrew;
Current trends in Biomedicine Talk given at a conference Microbiome role in health and disease 04.10.2012 Baeza, Spain Macpherson Andrew;
Cytokines 10th Joint Annual Meeting Talk given at a conference Innate and adaptive Immunity in Host Microbiota Mutualism 12.09.2012 Geneva, Switzerland Macpherson Andrew;
EMBO/EMPL Symposium Talk given at a conference New perspectives on immunity to infection 03.05.2012 Heidelberg, Germany Macpherson Andrew;


Associated projects

Number Title Start Funding scheme
124732 Investigation of the induction mechanisms and function of secretory IgA against commensal bacteria using reversible germ-free colonisation 01.04.2009 Project funding (Div. I-III)
136286 Recovery of intestinal homeostasis after microbial or immunological challenge 01.12.2011 Sinergia
160262 Secretory IgA in host-microbial reciprocity 01.04.2015 Project funding (Div. I-III)

Abstract

BACKGROUNDHealthy animals and humans co-exist with a dense microbiota in the lower intestine, so there are many more microbial than host cells in the body. There is an extensive and diverse molecular exchange between the microbiota and their host, although live microbes are mainly confined to the lumen of the intestine. The mucosal immune system is extensively adapted to the presence of the microbiota: we have shown that small numbers of commensal intestinal bacteria can be sampled by dendritic cells at the mucosal surface (Science 2004; 303, 1662) with the induction of compartmentalised mucosal immune responses of anti-commensal IgA (Science 2000; 288, 2222) and regulatory T cells (Immunity 2011; 34, 794). A serious problem in studying how mucosal immunity functions to maintain mutualism with live commensal intestinal microbes, was that induction of host mucosal immunity involved irreversible microbial colonisation of the intestine. We have solved this by engineering a bacterial strain of Escherichia coli with auxotrophic deletions that prevents it surviving in the germ-free intestine; so we can experimentally uncouple specific mucosal immune induction and intestinal microbial colonisation (Science 2010; 328, 1705) for functional gnotobiotic experiments.OBJECTIVESIn this grant we will address three facets of host microbial interaction, with a focus on the function of secretory IgA. 1. The way in which specific secretory IgA (SIgA) influences dynamics of bacterial proliferation, death, retention and shedding from the different intestinal segments. 2. How specific SIgA determines the ‘handshake’ between live intestinal microbes and their molecular products at the mucosal surface and above the inner mucus layer of the small and large intestines. 3. How the mucosal IgA plasma cell compartment size may be critical to determine the functional repertoire of SIgA against commensals, and whether any systemic antibody tolerance to commensals occurs during intestinal IgA induction in the face of mucosal-systemic immune compartmentalisation.METHODSOur method of reversible colonisation permits mucosal immune priming of specific antibacterial IgA secretion in germ-free animals: we will compare bacterial colonisation, replication, metabolism and shedding dynamics in different intestinal segments after challenge with replication-competent and incompetent bacteria. Using different germ-free mouse strains (e.g. C57BL/6 wild-type, JH-/- or IgA-/- antibody deficient, somatic hypermutation deficient, T cell deficient) we will determine the in vivo functional performance of the immune system in these experiments. Bacterial replication will be measured with IPTG-dependent plasmids and by metabolic labelling. Mass spectroscopy will assess penetration of 13C-labelled bacterial metabolites at the interface with the host.IMPACTMutualism between mammalian hosts and their commensal microbiota is critical for health, but poorly understood. In this grant we will use powerful axenic and gnotobiotic methodology to independently manipulate intestinal bacteria and host mucosal immunity to address this critical interface. Epidemiological studies show an importance of the microbiota in inflammatory bowel disease, obesity, autoimmunity, dyslipidaemia, endotoxaemia and malignancy. An improved understanding of the host-microbial handshake is fundamental to advances in human health.
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