Effector–host interactome map links type III secretion systems in healthy gut microbiomes to immune modulation
Nature Microbiology, vol. 11, pp. 442–460
Abstract
Pseudomonadota (formerly Proteobacteria) are prevalent in the commensal human gut microbiota, but also include many pathogens that rely on secretion systems to support pathogenicity by injecting proteins into host cells. Here we show that 80% of Pseudomonadota from healthy gut microbiomes also have intact type III secretion systems (T3SS). Candidate effectors predicted by machine learning display sequence and structural features that are distinct from those of pathogen effectors. Towards a systems-level functional understanding, we experimentally constructed a protein-protein meta-interactome map between human proteins and commensal effectors. Network analyses uncovered that effector-targeted neighbourhoods are enriched for genetic variation linked to microbiome-associated conditions, including autoimmune and metabolic diseases. Metagenomic analysis revealed effector enrichment in Crohn's disease but depletion in ulcerative colitis. Functionally, commensal effectors can translocate into human cells and modulate NF-κB signalling and cytokine secretion in vitro. Our findings indicate that T3SS contribute to microorganism-host cohabitation and that effector-host protein interactions may represent an underappreciated route by which commensal gut microbiota influences health.
Authors 43
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Centre National de la Recherche Scientifique · Inserm · Aix-Marseille Université · Theories and Approaches of Genomic Complexity · Architecture et Fonction des Macromolécules Biologiques
Affiliation as printed
Aix-Marseille University, CNRS, AFMB, UMR CNRS 7257, Turing Center for Living Systems, Marseille, France
Aix-Marseille University, INSERM, TAGC, UMR_S1090, Turing Center for Living Systems, Marseille, France
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, Aachen, Germany
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Department of Microbiology and Ecosystem Science, Research Network: Chemistry meets Microbiology, University of Vienna, Vienna, Austria
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Inserm · Aix-Marseille Université · M S Ramaiah University of Applied Sciences · Theories and Approaches of Genomic Complexity
Affiliation as printed
Aix-Marseille University, INSERM, TAGC, UMR_S1090, Turing Center for Living Systems, Marseille, France
Department of Biotechnology, Faculty of Life and Allied Health Sciences, Ramaiah University of Applied Sciences, Bangalore, India
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
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Harvard University · Dana-Farber Cancer Institute
Affiliation as printed
Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
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Affiliation as printed
Laboratory of Viral Interactomes, GIGA Institute, University of Liège, Liège, Belgium
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Ludwig-Maximilians-Universität München
Affiliation as printed
Dr von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Inserm · Aix-Marseille Université · Theories and Approaches of Genomic Complexity
Affiliation as printed
Aix-Marseille University, INSERM, TAGC, UMR_S1090, Turing Center for Living Systems, Marseille, France
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Inserm · Aix-Marseille Université · Theories and Approaches of Genomic Complexity
Affiliation as printed
Aix-Marseille University, INSERM, TAGC, UMR_S1090, Turing Center for Living Systems, Marseille, France
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Inserm · Aix-Marseille Université · Theories and Approaches of Genomic Complexity
Affiliation as printed
Aix-Marseille University, INSERM, TAGC, UMR_S1090, Turing Center for Living Systems, Marseille, France
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Inserm · Aix-Marseille Université · Theories and Approaches of Genomic Complexity
Affiliation as printed
Aix-Marseille University, INSERM, TAGC, UMR_S1090, Turing Center for Living Systems, Marseille, France
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Affiliation as printed
Research Unit Signaling and Translation, Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Research Unit Signaling and Translation, Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Helmholtz Munich · Ludwig-Maximilians-Universität München
Affiliation as printed
Dr von Hauner Children's Hospital, Department of Pediatrics, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany
German Center for Child and Adolescent Health (DZKJ), partner site Munich, Munich, Germany
Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
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Helmholtz Munich · Institute of Computational Biology · Technical University of Munich
Affiliation as printed
Department of Computer Science, TUM School of Computation, Information and Technology, Technical University of Munich, Garching, Germany
Institute of Computational Biology (ICB), Computational Health Center, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Universitätsklinikum Aachen · RWTH Aachen University
Affiliation as printed
Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH Aachen, Aachen, Germany
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Harvard University · Dana-Farber Cancer Institute
Affiliation as printed
Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
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Harvard University · Dana-Farber Cancer Institute
Affiliation as printed
Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA, USA
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA
Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
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New York University Abu Dhabi · University of Liège
Affiliation as printed
Laboratory of Algal Synthetic and Systems Biology, Division of Science, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
Laboratory of Viral Interactomes, GIGA Institute, University of Liège, Liège, Belgium
TERRA Teaching and Research Centre, University of Liège, Gembloux, Belgium
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Centre National de la Recherche Scientifique · Aix-Marseille Université · Architecture et Fonction des Macromolécules Biologiques
Affiliation as printed
Aix-Marseille University, CNRS, AFMB, UMR CNRS 7257, Turing Center for Living Systems, Marseille, France
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Affiliation as printed
Research Unit Signaling and Translation, Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Utrecht University · University Medical Center Utrecht
Affiliation as printed
Center for Translational Immunology, Pediatrics Department, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
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Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany
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Affiliation as printed
Department of Microbiology and Ecosystem Science, Research Network: Chemistry meets Microbiology, University of Vienna, Vienna, Austria
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Centre National de la Recherche Scientifique · Inserm · Aix-Marseille Université · Theories and Approaches of Genomic Complexity
Affiliation as printed
Aix-Marseille University, INSERM, TAGC, UMR_S1090, Turing Center for Living Systems, Marseille, France
CNRS, Marseille, France
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Andreas Zanzoni corresponding
Inserm · Aix-Marseille Université · Theories and Approaches of Genomic Complexity
Affiliation as printed
Aix-Marseille University, INSERM, TAGC, UMR_S1090, Turing Center for Living Systems, Marseille, France. andreas.zanzoni@univ-amu.fr
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Pascal Falter-Braun corresponding
Helmholtz Munich · Ludwig-Maximilians-Universität München
Affiliation as printed
Institute of Network Biology (INET), Molecular Targets and Therapeutics Center (MTTC), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany. pascal.falter-braun@helmholtz-munich.de
Microbe-Host Interactions, Faculty of Biology, Ludwig-Maximilians-Universität (LMU) München, Planegg-Martinsried, Germany. pascal.falter-braun@helmholtz-munich.de
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