title: Innate immune response to Streptococcus pyogenes depends on the combined activation of TLR13 and TLR2.
abstract: Innate immune recognition of the major human-specific Gram-positive pathogen Streptococcus pyogenes is not understood. Here we show that mice employ Toll-like receptor (TLR) 2- and TLR13-mediated recognition of S. pyogenes. These TLR pathways are non-redundant in the in vivo context of animal infection, but are largely redundant in vitro, as only inactivation of both of them abolishes inflammatory cytokine production by macrophages and dendritic cells infected with S. pyogenes. Mechanistically, S. pyogenes is initially recognized in a phagocytosis-independent manner by TLR2 and subsequently by TLR13 upon internalization. We show that the TLR13 response is specifically triggered by S. pyogenes rRNA and that Tlr13-/- cells respond to S. pyogenes infection solely by engagement of TLR2. TLR13 is absent from humans and, remarkably, we find no equivalent route for S. pyogenes RNA recognition in human macrophages. Phylogenetic analysis reveals that TLR13 occurs in all kingdoms but only in few mammals, including mice and rats, which are naturally resistant against S. pyogenes. Our study establishes that the dissimilar expression of TLR13 in mice and humans has functional consequences for recognition of S. pyogenes in these organisms.
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Fieber
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Marton
authors.initials: M
authors.lastname: Janos
authors.affiliation: Center for Integrative Bioinformatics Vienna, Max F. Perutz Laboratories, University of Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Tina
authors.initials: T
authors.lastname: Koestler
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Nina
authors.initials: N
authors.lastname: Gratz
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Li
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Virginia
authors.initials: V
authors.lastname: Castiglia
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Marion
authors.initials: M
authors.lastname: Aberle
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Sauert
authors.affiliation: Universitätsklinikum Freiburg, Universitäts-Hautklinik, Freiburg, Germany.
authors.forename: Mareike
authors.initials: M
authors.lastname: Wegner
authors.affiliation: Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille Université UM 2, Marseille, France.
authors.forename: Lena
authors.initials: L
authors.lastname: Alexopoulou
authors.affiliation: Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Kirschning
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Zhijian J
authors.initials: ZJ
authors.lastname: Chen
authors.affiliation: Center for Integrative Bioinformatics Vienna, Max F. Perutz Laboratories, University of Vienna, Medical University of Vienna, Vienna, Austria; Bioinformatics and Computational Biology, Faculty of Computer Science, University of Vienna, Vienna, Austria.
authors.forename: Arndt
authors.initials: A
authors.lastname: von Haeseler
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Vienna, Austria.
authors.forename: Pavel
authors.initials: P
authors.lastname: Kovarik
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D026901:Membrane Transport Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D010802:Phylogeny; D012329:RNA, Bacterial / Q000276:immunology; D013297:Streptococcus pyogenes / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*
chemical_list: D026901:Membrane Transport Proteins; D012329:RNA, Bacterial; C539093:Tlr13 protein, mouse; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; C512254:UNC93B1 protein, mouse