title: Type I interferon production induced by Streptococcus pyogenes-derived nucleic acids is required for host protection.
abstract: Streptococcus pyogenes is a Gram-positive human pathogen that is recognized by yet unknown pattern recognition receptors (PRRs). Engagement of these receptor molecules during infection with S. pyogenes, a largely extracellular bacterium with limited capacity for intracellular survival, causes innate immune cells to produce inflammatory mediators such as TNF, but also type I interferon (IFN). Here we show that signaling elicited by type I IFNs is required for successful defense of mice against lethal subcutaneous cellulitis caused by S. pyogenes. Type I IFN signaling was accompanied with reduced neutrophil recruitment to the site of infection. Mechanistic analysis revealed that macrophages and conventional dendritic cells (cDCs) employ different signaling pathways leading to IFN-beta production. Macrophages required IRF3, STING, TBK1 and partially MyD88, whereas in cDCs the IFN-beta production was fully dependent on IRF5 and MyD88. Furthermore, IFN-beta production by macrophages was dependent on the endosomal delivery of streptococcal DNA, while in cDCs streptococcal RNA was identified as the IFN-beta inducer. Despite a role of MyD88 in both cell types, the known IFN-inducing TLRs were individually not required for generation of the IFN-beta response. These results demonstrate that the innate immune system employs several strategies to efficiently recognize S. pyogenes, a pathogenic bacterium that succeeded in avoiding recognition by the standard arsenal of TLRs.
authors.affiliation: Max F. Perutz Laboratories, Department of Microbiology, Immunobiology and Genetics, University of Vienna, Vienna, Austria.
authors.forename: Nina
authors.initials: N
authors.lastname: Gratz
authors.forename: Harald
authors.initials: H
authors.lastname: Hartweger
authors.forename: Ulrich
authors.initials: U
authors.lastname: Matt
authors.forename: Franz
authors.initials: F
authors.lastname: Kratochvill
authors.forename: Marton
authors.initials: M
authors.lastname: Janos
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sigel
authors.forename: Barbara
authors.initials: B
authors.lastname: Drobits
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Li
authors.forename: Sylvia
authors.initials: S
authors.lastname: Knapp
authors.forename: Pavel
authors.initials: P
authors.lastname: Kovarik
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002481:Cellulitis / Q000382:microbiology / Q000401:mortality; D004269:DNA, Bacterial / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D020868:Gene Silencing; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3; D050835:Interferon Regulatory Factors; D016899:Interferon-beta / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D053594:Myeloid Differentiation Factor 88; D020556:Neutrophil Infiltration / Q000276:immunology; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D012329:RNA, Bacterial / Q000378:metabolism*; D034741:RNA, Small Interfering; D051192:Receptors, Pattern Recognition; D015398:Signal Transduction / Q000276:immunology; D013297:Streptococcus pyogenes / Q000235:genetics / Q000276:immunology*; D000099197:STING Protein
chemical_list: D004269:DNA, Bacterial; D050838:Interferon Regulatory Factor-3; D050835:Interferon Regulatory Factors; D016899:Interferon-beta; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D017346:Protein Serine-Threonine Kinases; D012329:RNA, Bacterial; D034741:RNA, Small Interfering; D051192:Receptors, Pattern Recognition; C498178:Irf5 protein, mouse; C507780:Myd88 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C498588:Tbk1 protein, mouse