title: Streptococcus pneumoniae stimulates a STING- and IFN regulatory factor 3-dependent type I IFN production in macrophages, which regulates RANTES production in macrophages, cocultured alveolar epithelial cells, and mouse lungs.
abstract: Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. In this study, we examine an innate immune recognition pathway that senses pneumococcal infection, triggers type I IFN production, and regulates RANTES production. We found that human and murine alveolar macrophages as well as murine bone marrow macrophages, but not alveolar epithelial cells, produced type I IFNs upon infection with S. pneumoniae. This response was dependent on the pore-forming toxin pneumolysin and appeared to be mediated by a cytosolic DNA-sensing pathway involving the adapter molecule STING and the transcription factor IFN regulatory factor 3. Indeed, DNA was present in the cytosol during pneumococcal infection as indicated by the activation of the AIM2 inflammasome, which is known to sense microbial DNA. Type I IFNs produced by S. pneumoniae-infected macrophages positively regulated gene expression and RANTES production in macrophages and cocultured alveolar epithelial cells in vitro. Moreover, type I IFNs controlled RANTES production during pneumococcal pneumonia in vivo. In conclusion, we identified an immune sensing pathway detecting S. pneumoniae that triggers a type I IFN response and positively regulates RANTES production.
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité University Medicine Berlin, 13353 Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Koppe
authors.forename: Katrin
authors.initials: K
authors.lastname: Högner
authors.forename: Jan-Moritz
authors.initials: JM
authors.lastname: Doehn
authors.forename: Holger C
authors.initials: HC
authors.lastname: Müller
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
authors.forename: Birgitt
authors.initials: B
authors.lastname: Gutbier
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauer
authors.forename: Thomas
authors.initials: T
authors.lastname: Pribyl
authors.forename: Sven
authors.initials: S
authors.lastname: Hammerschmidt
authors.forename: Jürgen
authors.initials: J
authors.lastname: Lohmeyer
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.forename: Bastian
authors.initials: B
authors.lastname: Opitz
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000276:immunology; D001426:Bacterial Proteins / Q000502:physiology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D018946:Chemokine CCL5 / Q000096:biosynthesis*; D018920:Coculture Techniques; D003600:Cytosol / Q000276:immunology / Q000378:metabolism; D004269:DNA, Bacterial / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D007370:Interferon Type I / Q000096:biosynthesis* / Q000502:physiology; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019899:Paracrine Communication / Q000276:immunology; D020545:Respiratory Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000276:immunology*; D013301:Streptolysins / Q000502:physiology; D000099197:STING Protein
chemical_list: D001426:Bacterial Proteins; D018946:Chemokine CCL5; D004269:DNA, Bacterial; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; D013301:Streptolysins; C530855:Sting1 protein, mouse; D000099197:STING Protein; C032290:plY protein, Streptococcus pneumoniae