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The role of intercellular signal transmission in innate immunity

Applicant Ablasser Andrea
Number 155984
Funding scheme SNSF Starting Grants
Research institution
Institution of higher education EPF Lausanne - EPFL
Main discipline Immunology, Immunopathology
Start/End 01.04.2015 - 31.03.2020
Approved amount 1'500'000.00
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Keywords (3)

Innate Immunology; Intracellular Signaling Pathways; Gap junction communication

Lay Summary (German)

Lead
Das angeborene Immunsystem hat vielfältige Strategien entwickelt um Pathogene zu bekämpfen. Die Koordination dieser Abwehrreaktion erfordert eine präzise Regulation der einzelnen Immunzellen untereinander. Das Ziel dieses Projektes ist zu untersuchen inwiefern die direkte Kommuniation einzelner Zellen über Gap Junctions den Prozess einer angeborenen Immunantwort beeinflusst.
Lay summary

Die Fähigkeit einzelnen Zellen untereinander Informationen auszutauschen und miteinander zu kollaborieren ist grundlegend für jede Immunantwort multizellulärer Organismen. Bei der Koordination dieses Informationsaustausches sind verschiedene Zytokine und Chemokine beteiligt, die von Zellen im Rahmen einer Infektion produziert werden. Zytokine, wie z.B. die Typ I Interferone, können über parakrine Signalwege benachbarte Zellen über stattfindenden Infektionen mit Pathogen informieren. In den letzten Jahren sind viele Rezeptoren und deren Signalwege beschrieben worden, die die Erkennung von Pathogen mit der Sekretion von Zytokinen in Zusammenhang bringen. Im Hinblick auf die Produktion von Typ I Interferonen hat sich dabei die Erkennung von Nukleinsäuren durch intrazelluläre Sensoren als ein zentraler Mechanismus herauskristallisiert. So wurde gezeigt, dass das Vorkommen intrazellulärer DNA einen Rezeptor namens zyklische GMP-AMP Synthase aktiviert, der daraufhin die Synthese des sekundären Botenstoffes zyklische GMP-AMP (GAMP) vorantreibt. Zyklisches GAMP bindet an den Zweitrezeptor STING was schließlich die Transkription verschiedene antiviraler Zytokine einleitet. Vor kurzem haben wir einen neuen Mechanismus entdeckt über den sich eine antivirale Immunantwort ausbreiten kann. Dabei haben wir festgestellt, dass zyklisches GAMP durch direkten Zellkontakt via Gap Juntions an benachbarte Zellen weitergegeben werden kann und in diesen eine Immunreaktion provoziert. Wir nehmen an, dass diese Art der interzellulären Kommunikation eine wichtige Funktion bei der Immunabwehr verschiedener Pathogen spielt und wir vermuten, dass weitere Rezeptoren des Immunsystems über die Fähigkeit verfügen Information über Gap junctions auszutauschen. Ein detailliertes Wissen darüber wie der interzelluläre Informationsaustausch abläuft ist nicht nur wichtig um das angeborene Immunsystem als Ganzes besser zu verstehen, sondern könnte auch dazu beitragen neue Therapiekonzepte für Infektionskrankheiten zu entwickeln.

Direct link to Lay Summary Last update: 24.11.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Regulation of cGAS- and RLR-mediated immunity to nucleic acids
Ablasser Andrea, Hur Sun (2020), Regulation of cGAS- and RLR-mediated immunity to nucleic acids, in Nature Immunology, 21(1), 17-29.
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.
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
, Innate Immune Sensing of Cytosolic Chromatin Fragments Through cGAS Promotes Senescence, in Nature Cell Biology, 1061-1070.

Collaboration

Group / person Country
Types of collaboration
Freddy Radtke, EPFL Switzerland (Europe)
- Publication
Beat Fierz, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Gisou van der Goot, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Jan Rehwinkel, University of Oxford Great Britain and Northern Ireland (Europe)
- Publication
Selman Sakar, EPFL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Andreas Villunger, Universität Innsbruck Austria (Europe)
- Publication
Lars Zender, Universität Tübingen Germany (Europe)
- Publication
Nicolas Thomä, FMI Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
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 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, London 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 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 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 Fribourg, 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-Transregio 84 Seminar Individual talk Intracellular DNA sensing during infection and beyond 26.01.2016 Berlin, Germany Ablasser Andrea;
Invited Talk, University of Freiburg Individual talk Intracellular DNA sensing during infection and disease 07.12.2015 Freiburg, Germany Ablasser Andrea;
2nd workshop on Dendritic cell biology Talk given at a conference Intracellular DNA sensing in infection and disease 23.11.2015 Marseille, France 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;
Invited Seminar, University of Geneva Individual talk Intracellular DNA sensing 02.11.2015 Genf, 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;
Deutsch-österreichischer AIDS Kongress Talk given at a conference Intracellular DNA sensing mechanisms 24.06.2015 Düsseldorf, Germany Ablasser Andrea;
3rd International Symposium of the CRC 900 Talk given at a conference Intracellular DNA sensing mechanisms during pathogen infection 28.05.2015 Hannover, Germany Ablasser Andrea;
Invited Talk, University of Erlangen Individual talk Intracellular DNA sensing mechanisms 24.04.2015 Erlangen, Germany Ablasser Andrea;
Keystone Symposium: Innate Immunity & Determinants of Microbial Pathogenesis Talk given at a conference Intracellular DNA sensing during infection with Mtb 19.04.2015 Olympic Valley, United States of America Ablasser Andrea;
Invited Seminar, University of Oxford Individual talk Intracellular DNA sensing mechanisms 01.04.2015 Oxford, Great Britain and Northern Ireland Ablasser Andrea;


Associated projects

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

Abstract

The innate immune response of multicellular organisms relies on the extraordinary capability of cells to collaborate via cell-to-cell communication. The coordination of cellular collaboration is primarily attributed to cytokines and chemokines, which are being secreted by pathogen-infected cells. Cytokines, such as type I interferons (IFNs), can alert non-infected cells to anticipate pathogen challenge through paracrine signaling. Moreover, cytokines serve to instruct specialized immune cells to contain and eradicate microbial infection. Several receptors and signaling pathways have been identified that connect pathogen sensing with the production of cytokines, with the cytosolic sensing of nucleic acids being exquisitely important for the activation of type I IFNs. Intracellular DNA is sensed by the nucleotidyltransferase cGAS, which catalyzes the synthesis of the 2nd messenger cGAMP. This molecule in turn activates the ER-resident receptor STING to induce the transcriptional up-regulation of type I IFNs and to promote an antiviral state. Recently, we have identified a novel mechanism, whereby antiviral immunity is transferred to non-infected cells in the absence paracrine signaling. Specifically, we have demonstrated that upon DNA sensing cGAS-produced cGAMP shuttles to bystander cells, where it confers antiviral immunity in a STING-dependent manner. We hypothesize that this particular route of intercellular communication serves an important role in antimicrobial immunity and we speculate that similar concepts apply to other pattern recognition receptor (PRR) signaling pathways. The goals of this proposal are to address the functional relevance of horizontal cGAMP transfer during DNA-virus infection and to characterize novel host factors involved in the regulation of this mechanism. We will also screen additional PRR-systems for their capability to regulate innate immune responses by mechanisms relying on gap junction communication. A detailed knowledge of PRR-triggered intercellular signalling mechanisms will not only be a critical step towards a global understanding of the innate immune response to pathogens but could also provide novel concepts for the treatment of infectious diseases.
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