Mycobacterium tuberculosis Differentially Activates cGAS- and Inflammasome-Dependent Intracellular Immune Responses through ESX-1
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Cytosolic detection of microbial products is essential for the initiation of an innate immune response against intracellular pathogens such as Mycobacterium tuberculosis (Mtb). During Mtb infection of macrophages, activation of cytosolic surveillance pathways is dependent on the mycobacterial ESX-1 secretion system and leads to type I interferon (IFN) and interleukin-1β (IL-1β) production. Whereas the inflammasome regulates IL-1β secretion, the receptor(s) responsible for the activation of type I IFNs has remained elusive. We demonstrate that the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) is essential for initiating an IFN response to Mtb infection. cGAS associates with Mtb DNA in the cytosol to stimulate cyclic GAMP (cGAMP) synthesis. Notably, activation of cGAS-dependent cytosolic host responses can be uncoupled from inflammasome activation by modulating the secretion of ESX-1 substrates. Our findings identify cGAS as an innate sensor of Mtb and provide insight into how ESX-1 controls the activation of specific intracellular recognition pathways.
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This phagosome-to-cytosol transition process has consequences for the host cell, such as induction of the cGAS/STING/TBK1/IRF-3/type I interferon signalling axis and NLRP3 inflammasome activation.
“an important cell biological process that has numerous consequences for the host cell, such as induc-tion of the cGAS/STING/TBK1/IRF-3/type I interferon signalling axis and NLRP3 inflammasome activation (69)(70)(71)(72)(73)(74)(75).”
From ESX/Type VII Secretion Systems—An Important Way Out for Mycobacterial Proteins (2019) · cites this paper as [70]
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Self-citation
- Authors
- Wassermann, R., Gulen, M. F., Sala, C., Perin, S. G., Lou, Y., Rybniker, J., Schmid-Burgk, J. L., Schmidt, T., Hornung, V., Cole, S. T., & Ablasser, A.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- University of Cologne (DE)
- University of Bonn (DE)
- Corresponding author
- Cole, Stewart T.
- Ablasser, Andrea
- ORCID
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 17
- Issue
- 6
- Pages
- 799-810
- ISSN
- 1931-3128 (ISSN-L)
- OpenAlex
- W1798681852
- Cited by
- 401
- References
- 46
- Citations by year
- 2026: 29 · 2025: 21 · 2024: 31 · 2023: 33 · 2022: 25 · 2021: 27 · 2020: 40 · 2019: 42 · 2018: 37 · 2017: 57 · 2016: 42 · 2015: 16
- FWCI
- 39.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_140778, 31003A_159836, 2014_A250)
- Else Kröner-Fresenius-Stiftung (31003A_140778, 31003A_159836, 2014_A250)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- Mycobacterium tuberculosis, cGAS, ESX-1 secretion system, inflammasome, type I interferon, IL-1β, cytosolic DNA sensing, macrophages, innate immune recognition, intracellular pathogens
- MeSH terms
- Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, DNA, Bacterial, Female, Humans, Interferon Type I, Male, Mycobacterium tuberculosis, Nucleotidyltransferases, Tuberculosis, Host-Pathogen Interactions
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