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Exploring intracellular DNA sensing mechanisms triggered by Mycobacterium tuberculosis

Applicant Ablasser Andrea
Number 159836
Funding scheme Project funding (Div. I-III)
Research institution Global Health Institute EPFL SV-DO
Institution of higher education EPF Lausanne - EPFL
Main discipline Immunology, Immunopathology
Start/End 01.06.2015 - 31.05.2019
Approved amount 566'438.00
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Keywords (3)

Innate Immunology; Nucleic acid sensing mechanims; Tuberculosis

Lay Summary (German)

Lead
Charakterisierung der angeborenen Immunantwort nach Infektion mit Mycobacterium tuberculosis
Lay summary

Tuberkulose stellt ein enormes, weltweites gesundheitliches Problem dar und ist jährlich für den Tod von ca. 1.5 Millionen Menschen verantwortlich. Die Erkrankung wird durch eine Infektion mit Mycobacterium tuberculosis (Mtb) ausgelöst und  manifestiert sich zunächst in der Lunge. Nach einer Infektion entwickelt sich allerdings nur in 5-10% der Fälle eine manifesten Erkrankung, wohingegen 90% der Infizierten keine Symptome aufweisen. Die Ursachen, die diesem Phänomen der asymptomatischen Infektion zu Grunde liegen, sind vielfältiger Natur, jedoch mehren sich Hinweise, dass die Aktivierung einer ausgeglichen angeborenen Immunantwort dabei eine wesentliche Rolle spielt. Insbesondere das durch die Infektion hervorgerufene Zytokinmilieu hat entscheidend Einfluss auf den Verlauf der Infektion und dem daraus resultierenden Krankheitsbild. Dabei ist bekannt, dass Typ I Interferone die Ausbreitung der Mykobakterien unterstützen und sich ungünstig auf den Erkrankungsverlauf auswirken. Kürzlich haben wir den DNA Rezeptor zyklische GMP-AMP Synthase (cGAS) als alleinigen, für die Interferonproduktion verantwortlichen Sensor für Mtb identifiziert. Wir konnten nachweisen, dass cGAS während einer Infektion mit Mtb im Zytoplasma infizierter Makrophagen aktiviert wird und den Zweitbotenstoff zyklisches GMP-AMP (cGAMP) produziert. cGAMP bindet wiederum an den Rezeptor Stimulator of interferon genes (STING) und löst dadurch eine  Signalkaskade aus die zur Produktion von Typ I Interferon führt. Basierend auf diesen Ergebnissen ist das Ziel dieses Forschungsprojektes den genauen Mechanismus der Aktivierung von cGAS durch Mtb herauszuarbeiten. Ferner suchen wir mittels eines High-throughput Screens chemische Verbindungen zu identifizieren, die die cGAS-STING-Signalkaskade spezifisch blockieren. Wir glauben, dass sich derartige Moleküle aufgrund der Blockade der probakteriellen Interferone als neuartige Therapeutika im Kampf gegen Tuberkulose erweisen könnten.

Direct link to Lay Summary Last update: 30.03.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
cGAS in action: Expanding roles in immunity and inflammation
Ablasser Andrea, Chen Zhijian J. (2019), cGAS in action: Expanding roles in immunity and inflammation, in Science, 363(6431), eaat8657-eaat8657.
Innate immunosensing of DNA in cellular senescence
Glück Selene, Ablasser Andrea (2019), Innate immunosensing of DNA in cellular senescence, in Current Opinion in Immunology, 56, 31-36.
Targeting STING with covalent small-molecule inhibitors
Haag Simone M., Gulen Muhammet F., Reymond Luc, Gibelin Antoine, Abrami Laurence, Decout Alexiane, Heymann Michael, van der Goot F. Gisou, Turcatti Gerardo, Behrendt Rayk, Ablasser Andrea (2018), Targeting STING with covalent small-molecule inhibitors, in Nature, 559(7713), 269-273.
Signalling strength determines proapoptotic functions of STING
Gulen Muhammet F., Koch Ute, Haag Simone M., Schuler Fabian, Apetoh Lionel, Villunger Andreas, Radtke Freddy, Ablasser Andrea (2017), Signalling strength determines proapoptotic functions of STING, in Nature Communications, 8(1), 427-427.
Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence.
Ablasser Andrea, Glück Selene, GueyBaptiste, GulenMuhammet, WolterKatharina, KangTae-Won, SchmackeNiklas, BridgemanAnne, RehwinkelJan, ZenderLars (2017), Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence., in Nature Cell Biology, 1061.
The role of cGAS in innate immunity and beyond
Ablasser Andrea, Gulen Muhammed F. (2016), The role of cGAS in innate immunity and beyond, in Journal of Molecular Medicine, 94(10), 1085-1093.
Mycobacterium tuberculosis Differentially Activates cGAS- and Inflammasome-Dependent Intracellular Immune Responses through ESX-1
Wassermann Ruth, Gulen Muhammet F., Sala Claudia, Perin Sonia Garcia, Lou Ye, Rybniker Jan, Schmid-Burgk Jonathan L., Schmidt Tobias, Hornung Veit, Cole Stewart T., Ablasser Andrea (2015), Mycobacterium tuberculosis Differentially Activates cGAS- and Inflammasome-Dependent Intracellular Immune Responses through ESX-1, in Cell Host & Microbe, 17(6), 799-810.

Collaboration

Group / person Country
Types of collaboration
Prof. van der Goot, EPFL Switzerland (Europe)
- Publication
Rayk Behrendt, University of Dresden Germany (Europe)
- Publication
Prof. Dr. Freddy Radtke, EPFL Switzerland (Europe)
- Publication
Prof. Lars Zender, University of Tübingen Germany (Europe)
- Publication
Prof. Jan Rehwinkel, University of Oxford Great Britain and Northern Ireland (Europe)
- Publication
Prof. Dr. Stewart Cole, EPFL 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
FASEB: The Protein Lipidation Conference Talk given at a conference Mechanisms of intracellular DNA sensing 07.07.2019 Olean, United States of America Ablasser Andrea;
Novel Concepts in Immunology Talk given at a conference Mechanisms of intracellular DNA sensing 12.06.2019 Tübingen, Germany Ablasser Andrea;
Immunooncology Symposium, US, Boston Talk given at a conference Mechanisms of intracellular DNA sensing 06.06.2019 Boston, United States of America Ablasser Andrea;
Conference on Molecular Mechanisms of Inflammation Talk given at a conference Mechanisms of intracellular DNA sensing 04.06.2019 Trondheim, Norway Ablasser Andrea;
MKFZ Charite Berlin, Learning from the Yins and Yangs in Cancer Talk given at a conference Mechanisms of intracellular DNA sensing 25.05.2019 Berlin, Germany Ablasser Andrea;
Cell Press Immunity - Immunity Unplugged Talk given at a conference Mechanisms of intracellular DNA sensing 09.05.2019 San Diego, United States of America Ablasser Andrea;
Annual Meeting of the American Association of Immunologists Talk given at a conference Mechanisms of intracellular DNA sensing 09.05.2019 San Diego, United States of America Ablasser Andrea;
10th International Congress FMF and Systemic Autoinflammatory Diseases Talk given at a conference Mechanisms of intracellular DNA sensing 31.03.2019 Genoa, Italy Ablasser Andrea;
AEK International Cancer Conference Talk given at a conference Mechanisms of intracellular DNA sensing 28.03.2019 Heidelberg, Germany Ablasser Andrea;
Frontiers in Medicinal Chemistry Talk given at a conference Mechanisms of intracellular DNA sensing 25.03.2019 Würzburg, Germany Ablasser Andrea;
9th International Lorne Infection & Immunity Conference 2019 Talk given at a conference Mechanisms of intracellular DNA sensing 02.02.2019 Lorne, Australia Ablasser Andrea;
Mini-Symposium - Stanford Brain Rejuvenation project Talk given at a conference Mechanisms of intracellular DNA sensing 01.02.2019 Stanford, United States of America Ablasser Andrea;
International Cell Senescence Association (ICSA) Conferences 2018 Talk given at a conference Mechanisms of intracellular DNA sensing 08.07.2018 Montreal, Canada Ablasser Andrea;
EMBO|EMBL Symposium: Innate Immunity in Host-Pathogen Interactions Talk given at a conference Mechanisms of intracellular DNA sensing 24.06.2018 Heidelberg, Germany Ablasser Andrea;
DINGO Meeting: DNA Damage Response, Innate Immunity & Inflammation, France, Paris, Institute Curie Talk given at a conference Mechanisms of intracellular DNA sensing 21.06.2018 Paris, France Haag Simone Margret;
TOLL2018 - Editing Innate Immunity Talk given at a conference Mechanisms of intracellular DNA sensing 06.06.2018 Porto, Portugal Ablasser Andrea;
International Hepatitis Symposium Heidelberg Talk given at a conference Mechanisms of intracellular DNA sensing 17.05.2018 Heidelberg, Germany Ablasser Andrea;
Spring Symposium - Harvard Digestive Disease Center Talk given at a conference Mechanisms of intracellular DNA sensing 10.04.2018 Boston, United States of America Ablasser Andrea;
Germany Society of Virology - Annual Meeting Talk given at a conference Mechanisms of intracellular DNA sensing 15.03.2018 Würzburg, Germany Ablasser Andrea;
ADF Symposium Talk given at a conference Mechanisms of intracellular DNA sensing 09.03.2018 Zürich, Switzerland Ablasser Andrea;
Cold Spring Harbor Asia meeting on Inflammation: Basic mechanisms and relevant Diseases Talk given at a conference Mechanisms of intracellular DNA sensing 12.12.2017 Suzhou, China Ablasser Andrea;
Annual Meeting of the German Society for Aging Research Talk given at a conference Mechanisms of intracellular DNA sensing 01.12.2017 Cologne, Germany Ablasser Andrea;
Annual Meeting International Cytokine&Interferon Society Talk given at a conference Mechanisms of intracellular DNA sensing 30.10.2017 Kanazawa, Japan Ablasser Andrea;
2nd Molecular Biology of Ageing Meeting Talk given at a conference Mechanisms of intracellular DNA sensing 11.10.2017 Groningen, Netherlands Ablasser Andrea;
Nature Conference on Inflammatory Diseases Talk given at a conference Mechanisms of intracellular DNA sensing 18.09.2017 Beijing, China Ablasser Andrea;
KFO 249 Symposium Talk given at a conference Mechanisms of intracellular DNA sensing 31.08.2017 Dresden, Germany Ablasser Andrea;
Aegean Conferences, 14th International Conference on Innate Immunity Talk given at a conference Intracellular DNA sensing during infection and beyond 20.06.2017 Kreta, Greece Ablasser Andrea;
9th Blizard Institute HIV Symposium Talk given at a conference Intracellular DNA sensing mechanisms during infection and beyond 15.06.2017 London, Great Britain and Northern Ireland Ablasser Andrea;
NCCR Chemical Biology, Switzerland Talk given at a conference Targeting innate DNA sensing with small-molecules 07.06.2017 Villars-sur-Ollon, Switzerland Ablasser Andrea;
Invited Seminar at UCB Individual talk Intracellular 05.06.2017 London, Great Britain and Northern Ireland Ablasser Andrea;
Mycobacteries 2017, 5ème conférence MYCOCLUB Talk given at a conference Intracellular DNA sensing mechnisms during infection and beyond 29.05.2017 Monitgny-le-Bretonneux, France Ablasser Andrea;
International Cell Senescence Association (ICSA) Conferences 2017 Talk given at a conference Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence 16.05.2017 Paris, France Ablasser Andrea;
Keystone Symposium: Pattern Recognition Signaling: From Innate Immunity to Inflammatory Disease Talk given at a conference Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence 19.03.2017 Banff, Canada Ablasser Andrea;
1st International Symposium on Immune Response in Cancer and Infection Talk given at a conference Intracellular DNA sensing mechanisms during infection and beyond 13.02.2017 Lyon, France Ablasser Andrea;
Celebrating 20 years Nucleic Acid Immunity Talk given at a conference Cytosolic DNA sensing 10.12.2016 Bonn, Germany Ablasser Andrea;
Invited Seminar Novartis Campus Individual talk Intracellular DNA sensing during Infection and beyond 28.11.2016 Basel, Switzerland Ablasser Andrea;
Invited Seminar Unversity of Aarhus Individual talk Intracellular DNA sensing mechanisms during infection and beyond 26.10.2016 Aarhus, Denmark Ablasser Andrea;
46th Annual Meeting Deutsche Gesellschaft für Immunologie Talk given at a conference Intracellular DNA sensing during infection and beyond 28.09.2016 Hamburg, Germany Ablasser Andrea;
Max Planck Symposium Talk given at a conference Intracellular DNA sensing mechanisms during infection with Mtb 23.09.2016 Würzburg, Germany Ablasser Andrea;
Max Planck Symposium, Germany Talk given at a conference Intracellular DNA sensing during infection and beyond 23.09.2016 Würzburg, Germany Ablasser Andrea;
French Dendritic Cell Society Talk given at a conference Intracellular DNA sensing mechanisms during infection and beyond 19.09.2016 Paris, France Ablasser Andrea;
15th Awaji International Forum on Infection and Immunity Talk given at a conference Intracellular DNA sensing mechanisms during infection and beyond 06.09.2016 Awaji, Japan Ablasser Andrea;
Invited Seminar, University of Kyoto Individual talk Intracellular DNA sensing mechanisms during infection and beyond 05.09.2016 Kyoto, Japan Ablasser Andrea;
A symposium in memory of Jean Lindenmann Talk given at a conference Intracellular DNA sensing during infection and beyond 25.08.2016 Zürich, Switzerland Ablasser Andrea;
Gordon Research Conference 2016: Immunochemistry and Immunobiology Talk given at a conference Intracellular DNA sensing during infection and beyond 19.06.2016 Ciocco, Italy Ablasser Andrea;
33. Arbeitstagung der Pädiatrischen Immunologen, Switzerland Talk given at a conference Intracellular DNA sensing during infection and autoinflammation 05.05.2016 Ittingen, Switzerland Ablasser Andrea;
Fondation Mérieux Conference: Mechanisms behind chronic infecionts Talk given at a conference Intracellular DNA sensing mechanisms during infection with Mtb 02.05.2016 Veyrier-du-Lac, France Ablasser Andrea;
RNA and Infection Talk given at a conference Intracellular DNA sensing during infection and beyond 28.04.2016 Würzburg, Germany Ablasser Andrea;
Invited Seminar, Universität Fribourg Individual talk Intracellular DNA sensing during infection and beyond 19.04.2016 Freiburg, Switzerland Ablasser Andrea;
Invited Talk, Max-Planck-Institute of Infection Biology Individual talk Intracellular DNA sensing mechanisms 27.01.2016 Berlin, Germany Ablasser Andrea;
SFB-TR84 "Innate Immunity in the Lung" Individual talk Intracellular DNA sensing during infection and beyond 26.01.2016 Berlin, Germany Ablasser Andrea;
University of Freiburg Individual talk Intracellular DNA sensing during infection and disease 07.12.2015 Freiburg, Switzerland Ablasser Andrea;
Paul Ehrlich Centenary of death Talk given at a conference Intracellular DNA sensing during infection and beyond 22.11.2015 Frankfurt, Germany Ablasser Andrea;
2nd workshop on Dendritic cell biology Talk given at a conference Intracellular DNA sensing in infection and disease 03.11.2015 Marseille, France Ablasser Andrea;
Invited Seminar, University of Geneva Individual talk Intracellular DNA sensing 02.11.2015 Geneva, Switzerland Ablasser Andrea;
Invited Talk, University and CNRS Orléans Individual talk Intracellular DNA sensing during infection with MTb 14.10.2015 Orléans, France Ablasser Andrea;
TOLL Meeting 2015 Talk given at a conference Intracellular DNA sensing mechanisms during infection with Mtb 30.09.2015 Marbella, Spain Ablasser Andrea;
German-Austrian AIDS Congress Talk given at a conference Intracellular DNA sensing mechanisms 24.06.2015 Düsseldorf, Germany Ablasser Andrea;


Awards

Title Year
Prix Zonta 2019
ACTERIA Early Career Research Prize in Immunology 2018
Eppendorf Award for Young European Investigators 2018
National Latsis Prize 2018

Associated projects

Number Title Start Funding scheme
188759 Exploring the link between senescence and inflammation 01.04.2020 Project funding (Div. I-III)

Abstract

Understanding the immune response to Mycobacterium tuberculosis (Mtb) is a challenging scientific task with high relevance for a large part of the human population. Part of this challenge arises from the fact that immunity triggered by mycobacterial infection is highly complex mobilizing various types of both protective but also immunomodulatory host responses at the same time. Recent evidence has uncovered that the production of inflammatory cytokines is required for resistance against Mtb and that this part of the host response constitutes a critical factor to limit the infectious process. In contrast, cytokines from the family of type I interferons (IFNs) were found to exert pro-bacterial effects and even promote development of the disease, highlighting a broad physiological role for these cytokines in host defense to Mtb. But while the mechanisms of the innate immune system responsible for the production of inflammatory cytokine have been fairly well characterized, the host sensor(s) responsible for eliciting type I IFNs have just recently come into focus. In our current work we show that Mtb infection activates the DNA sensor cyclic GMP-AMP synthase (cGAS) to produce the 2nd messenger molecule cGAMP, which binds to and activates the receptor Stimulator of interferon genes (STING) to induce type I IFN transcription. These results demonstrate that cGAS is a non-redundant, innate sensor of Mtb with important consequences for understanding mycobacterial pathogenesis. On the basis of this work, the primary goal of this research proposal is to further improve our current knowledge of the molecular mechanisms by which Mtb elicits type I IFN responses and to transfer this knowledge towards developing novel host-directed therapeutic approaches for tuberculosis treatment.
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