title: Group A streptococcus activates type I interferon production and MyD88-dependent signaling without involvement of TLR2, TLR4, and TLR9.
abstract: Bacterial pathogens are recognized by the innate immune system through pattern recognition receptors, such as Toll-like receptors (TLRs). Engagement of TLRs triggers signaling cascades that launch innate immune responses. Activation of MAPKs and NF-kappaB, elements of the major signaling pathways induced by TLRs, depends in most cases on the adaptor molecule MyD88. In addition, Gram-negative or intracellular bacteria elicit MyD88-independent signaling that results in production of type I interferon (IFN). Here we show that in mouse macrophages, the activation of MyD88-dependent signaling by the extracellular Gram-positive human pathogen group A streptococcus (GAS; Streptococcus pyogenes) does not require TLR2, a receptor implicated in sensing of Gram-positive bacteria, or TLR4 and TLR9. Redundant engagement of either of these TLR molecules was excluded by using TLR2/4/9 triple-deficient macrophages. We further demonstrate that infection of macrophages by GAS causes IRF3 (interferon-regulatory factor 3)-dependent, MyD88-independent production of IFN. Surprisingly, IFN is induced also by GAS lacking slo and sagA, the genes encoding cytolysins that were shown to be required for IFN production in response to other Gram-positive bacteria. Our data indicate that (i) GAS is recognized by a MyD88-dependent receptor other than any of those typically used by bacteria, and (ii) GAS as well as GAS mutants lacking cytolysin genes induce type I IFN production by similar mechanisms as bacteria requiring cytoplasmic escape and the function of cytolysins.
authors.affiliation: Max F Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Vienna, Austria.
authors.forename: Nina
authors.initials: N
authors.lastname: Gratz
authors.forename: Maria
authors.initials: M
authors.lastname: Siller
authors.forename: Barbara
authors.initials: B
authors.lastname: Schaljo
authors.forename: Zaid A
authors.initials: ZA
authors.lastname: Pirzada
authors.forename: Irene
authors.initials: I
authors.lastname: Gattermeier
authors.forename: Ivo
authors.initials: I
authors.lastname: Vojtek
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Kirschning
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charpentier
authors.forename: Pavel
authors.initials: P
authors.lastname: Kovarik
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D007249:Inflammation / Q000378:metabolism; D007370:Interferon Type I / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013297:Streptococcus pyogenes; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D007370:Interferon Type I; D053594:Myeloid Differentiation Factor 88; D050794:STAT1 Transcription Factor; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9