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Nat Microbiol. 2019 Apr;4(4):701-713. doi: 10.1038/s41564-019-0367-z. Epub 2019 Feb 25.

Intracellular bacteria engage a STING-TBK1-MVB12b pathway to enable paracrine cGAS-STING signalling.

Author information

1
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
2
Max F. Perutz Laboratories, Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria.
3
Experimental Systems Immunology, Max Planck Institute of Biochemistry, Munich, Germany.
4
Department of Chemistry, Aarhus University, Aarhus, Denmark.
5
Center for DNA Nanotechnology, Aarhus University, Aarhus, Denmark.
6
Interdisciplinary Nanoscience Center, Aarhus University, Aarhus, Denmark.
7
CIRI, Inserm, CNRS, Ecole Normale Supérieure Lyon and University Claude Bernard Lyon 1, Lyon, France.
8
Institute for Lung Research, German Center for Lung Research, Universities of Giessen and Marburg Lung Centre, Philipps-University Marburg, Marburg, Germany.
9
Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
10
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
11
Department of Biomedicine, Aarhus University, Aarhus, Denmark. srp@biomed.au.dk.

Abstract

The innate immune system is crucial for eventual control of infections, but may also contribute to pathology. Listeria monocytogenes is an intracellular Gram-positive bacteria and a major cause of food-borne disease. However, important knowledge on the interactions between L. monocytogenes and the immune system is still missing. Here, we report that Listeria DNA is sorted into extracellular vesicles (EVs) in infected cells and delivered to bystander cells to stimulate the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway. This was also observed during infections with Francisella tularensis and Legionella pneumophila. We identify the multivesicular body protein MVB12b as a target for TANK-binding kinase 1 phosphorylation, which is essential for the sorting of DNA into EVs and stimulation of bystander cells. EVs from Listeria-infected cells inhibited T-cell proliferation, and primed T cells for apoptosis. Collectively, we describe a pathway for EV-mediated delivery of foreign DNA to bystander cells, and suggest that intracellular bacteria exploit this pathway to impair antibacterial defence.

PMID:
30804548
DOI:
10.1038/s41564-019-0367-z

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