title: Group B Streptococcus Degrades Cyclic-di-AMP to Modulate STING-Dependent Type I Interferon Production.
abstract: Induction of type I interferon (IFN) in response to microbial pathogens depends on a conserved cGAS-STING signaling pathway. The presence of DNA in the cytoplasm activates cGAS, while STING is activated by cyclic dinucleotides (cdNs) produced by cGAS or from bacterial origins. Here, we show that Group B Streptococcus (GBS) induces IFN-β production almost exclusively through cGAS-STING-dependent recognition of bacterial DNA. However, we find that GBS expresses an ectonucleotidase, CdnP, which hydrolyzes extracellular bacterial cyclic-di-AMP. Inactivation of CdnP leads to c-di-AMP accumulation outside the bacteria and increased IFN-β production. Higher IFN-β levels in vivo increase GBS killing by the host. The IFN-β overproduction observed in the absence of CdnP is due to the cumulative effect of DNA sensing by cGAS and STING-dependent sensing of c-di-AMP. These findings describe the importance of a bacterial c-di-AMP ectonucleotidase and suggest a direct bacterial mechanism that dampens activation of the cGAS-STING axis.
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Warrison A
authors.initials: WA
authors.lastname: Andrade
authors.affiliation: Institut Pasteur, Unité de Biologie des Bactéries Pathogènes à Gram-Positif, 75724 Paris, France; Centre National de la Recherche Scientifique (CNRS) ERL 3526, 75724 Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Firon
authors.affiliation: Institute of Molecular Medicine, Universitätsklinikum Bonn, Bonn 53127, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Institute of Molecular Medicine, Universitätsklinikum Bonn, Bonn 53127, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Evelyn A
authors.initials: EA
authors.lastname: Kurt-Jones
authors.affiliation: Institut Pasteur, Unité de Biologie des Bactéries Pathogènes à Gram-Positif, 75724 Paris, France; Centre National de la Recherche Scientifique (CNRS) ERL 3526, 75724 Paris, France. Electronic address: patrick.trieu-cuot@pasteur.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Trieu-Cuot
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Innate Immunity, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: douglas.golenbock@umassmed.edu.
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.affiliation: Institut Pasteur, Unité de Biologie des Bactéries Pathogènes à Gram-Positif, 75724 Paris, France; Centre National de la Recherche Scientifique (CNRS) ERL 3526, 75724 Paris, France.
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Kaminski
mesh_terms: D001711:Biotransformation; D015226:Dinucleoside Phosphates / Q000378:metabolism*; D057131:Immune Evasion; D007370:Interferon Type I / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D011755:Pyrophosphatases / Q000378:metabolism*; D013292:Streptococcus agalactiae / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D000099197:STING Protein
chemical_list: D015226:Dinucleoside Phosphates; D007370:Interferon Type I; D008565:Membrane Proteins; D011755:Pyrophosphatases; C532857:STING1 protein, human; D000099197:STING Protein; C528998:cyclic diadenosine phosphate; C092064:ectonucleotide pyrophosphohydrolase
keywords: Streptococcus agalactiae; c-di-AMP; cGAS; ectonucleotidase; interferon-β