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Secretory IgA in host-microbial reciprocity

English title Secretory IgA in host-microbial reciprocity
Applicant Macpherson Andrew
Number 160262
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 01.04.2015 - 31.03.2018
Approved amount 793'061.00
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Keywords (4)

host-microbial mutualism; IgA; intestine; commensal bacteria

Lay Summary (German)

Lead
Unser Dickdarm ist mit Milliarden von verschiedenen gutartigen Bakterien besiedelt. Zusammen bilden diese Bakterien das sogenannte Mikrobiom welches einen starken Einfluss auf unsere Gesundheit hat. Das Mikrobiom hilft auch unsere Nahrung zu verdauen und produziert zum Beispiel wichtige Vitamine. Dieses Projekt untersucht wie unser Immunsystem diese gutartigen Bakterien beeinflusst.
Lay summary

In dieser Studie untersuchen wir wie der Antikörper IgA im Darm das Mikrobiom beeinflusst. IgA ist der im Körper am meisten produzierte Antikörper. Seine genaue Funktion im Zusammenhang mit dem Mikrobiom ist jedoch weiterhin unklar. IgA Antikörper kommen unter anderem in der Darmschleimhaut vor, wo sie als Schutzbarriere gegen Krankheitserreger, die über die Nahrung in den Körper gelangen, agieren.

Wir möchten herausfinden wie die IgA-Antikörper welche in den Darm sekretiert werden das gesunde Mikrobiom kontrollieren und inwiefern dies Antikörper mit bakteriellem Molekülen, im Gegensatz zu den Bakterien selber, interagieren. Zu diesem Zweck verwenden wir spezifisch modifizierte Testbakterien, die nur für eine kurze Zeit im Darm verbleiben können und danach wieder verschwinden. Dies erlaubt uns die Reaktion des Immunsystems im Darm gegen diese Bakterien zu studieren und wie diese Immunreaktionen die Zusammensetzung und Dynamik des Mikrobioms beeinflussen.

Unsere Untersuchungen werden dazu Beitragen dass wir das gesunde Zusammenspiel zwischen uns und unserem Mikrobiom besser verstehen. 

 

Direct link to Lay Summary Last update: 23.04.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
IgA Function in Relation to the Intestinal Microbiota
Macpherson Andrew J., Yilmaz Bahtiyar, Limenitakis Julien P., Ganal-Vonarburg Stephanie C. (2018), IgA Function in Relation to the Intestinal Microbiota, in Annual Review of Immunology, 36(1), 359-381.
Do the Microbiota Influence Vaccines and Protective Immunity to Pathogens?Issues of Sovereignty, Federalism, and Points-Testing in the Prokaryotic and Eukaryotic Spaces of the Host-Microbial Superorganism
Macpherson Andrew J. (2018), Do the Microbiota Influence Vaccines and Protective Immunity to Pathogens?Issues of Sovereignty, Federalism, and Points-Testing in the Prokaryotic and Eukaryotic Spaces of the Host-Microbial Superorganism, in Cold Spring Harbor Perspectives in Biology, 10(2), a029363-a029363.
How nutrition and the maternal microbiota shape the neonatal immune system
Macpherson Andrew J., de Agüero Mercedes Gomez, Ganal-Vonarburg Stephanie C. (2017), How nutrition and the maternal microbiota shape the neonatal immune system, in Nature Reviews Immunology, 17(8), 508-517.
Genome-guided design of a defined mouse microbiota that confers colonization resistance against Salmonella enterica serovar Typhimurium
Brugiroux Sandrine, Beutler Markus, Pfann Carina, Garzetti Debora, Ruscheweyh Hans-Joachim, Ring Diana, Diehl Manuel, Herp Simone, Lötscher Yvonne, Hussain Saib, Bunk Boyke, Pukall Rüdiger, Huson Daniel H., Münch Philipp C., McHardy Alice C., McCoy Kathy D., Macpherson Andrew J., Loy Alexander, Clavel Thomas, Berry David, Stecher Bärbel (2017), Genome-guided design of a defined mouse microbiota that confers colonization resistance against Salmonella enterica serovar Typhimurium, in Nature Microbiology, 2(2), 16215-16215.
The Liver at the Nexus of Host-Microbial Interactions
Macpherson Andrew J., Heikenwalder Mathias, Ganal-Vonarburg Stephanie C. (2016), The Liver at the Nexus of Host-Microbial Interactions, in Cell Host & Microbe, 20(5), 561-571.
Complete Genome Sequences of 12 Species of Stable Defined Moderately Diverse Mouse Microbiota 2: TABLE 1
Uchimura Yasuhiro, Wyss Madeleine, Brugiroux Sandrine, Limenitakis Julien P., Stecher Bärbel, McCoy Kathy D., Macpherson Andrew J. (2016), Complete Genome Sequences of 12 Species of Stable Defined Moderately Diverse Mouse Microbiota 2: TABLE 1, in Genome Announcements, 4(5), e00951-16-e00951-16.
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.
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), 8292-8292.
The bilateral responsiveness between intestinal microbes and IgA
Macpherson Andrew J., Köller Yasmin, McCoy Kathy D. (2015), The bilateral responsiveness between intestinal microbes and IgA, in Trends in Immunology, 36(8), 460-470.
Standardised animal models of host microbial mutualism
Macpherson A J, McCoy K D (2015), Standardised animal models of host microbial mutualism, in Mucosal Immunology, 8(3), 476-486.

Collaboration

Group / person Country
Types of collaboration
Uwe Sauer/ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Hedda Wardemann, DKFZ, Heidelberg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
154414 The Host-Microbial Superorganism 01.01.2015 Sinergia
179479 The sequence of functional public and private antibody repertoire development in response to transient exposures to non-pathogenic intestinal microbes 01.10.2018 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)

Abstract

Induction of immunoglobulin (Ig)A is a hallmark response of mammals to environmental microbial colonisation of body surfaces. IgA is the most abundant antibody isotype, mostly secreted across mucous membranes. Many aspects of intestinal IgA function remain open, including its relative role in modulating the microbiota composition or position, compared with protecting the epithelial surface from incursion of live microbes or their molecular products. In this project we will address intestinal IgA function using our reversible germ-free system that uncouples IgA induction from colonisation by live microbes. We will use metabolomic stable-isotope tracing following challenge with the 13C-labelled E.coli, with and without pre-induced specific IgA, to distinguish protection from penetration of (13C) microbial products or the resultant (12C) host metabolic response. We will extend the range of commensal intestinal bacteria available for reversible IgA induction and investigate the roles of antibody affinity maturation and anti-bacterial specificity to achieve host microbial mutualism.
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