title: Human TLR8 senses UR/URR motifs in bacterial and mitochondrial RNA.
abstract: Toll-like receptor (TLR) 13 and TLR2 are the major sensors of Gram-positive bacteria in mice. TLR13 recognizes Sa19, a specific 23S ribosomal (r) RNA-derived fragment and bacterial modification of Sa19 ablates binding to TLR13, and to antibiotics such as erythromycin. Similarly, RNase A-treated Staphylococcus aureus activate human peripheral blood mononuclear cells (PBMCs) only via TLR2, implying single-stranded (ss) RNA as major stimulant. Here, we identify human TLR8 as functional TLR13 equivalent that promiscuously senses ssRNA. Accordingly, Sa19 and mitochondrial (mt) 16S rRNA sequence-derived oligoribonucleotides (ORNs) stimulate PBMCs in a MyD88-dependent manner. These ORNs, as well as S. aureus-, Escherichia coli-, and mt-RNA, also activate differentiated human monocytoid THP-1 cells, provided they express TLR8. Moreover, Unc93b1(-/-)- and Tlr8(-/-)-THP-1 cells are refractory, while endogenous and ectopically expressed TLR8 confers responsiveness in a UR/URR RNA ligand consensus motif-dependent manner. If TLR8 function is inhibited by suppression of lysosomal function, antibiotic treatment efficiently blocks bacteria-driven inflammatory responses in infected human whole blood cultures. Sepsis therapy might thus benefit from interfering with TLR8 function.
authors.affiliation: Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Krüger
authors.affiliation: Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Oldenburg
authors.affiliation: Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Chiranjeevi
authors.initials: C
authors.lastname: Chebrolu
authors.affiliation: Genome Informatics, Institute of Human Genetics, University of Duisburg-Essen, Essen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Beisser
authors.affiliation: Centre of Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Kolter
authors.affiliation: Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Sigmund
authors.affiliation: Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinmann
authors.affiliation: Clinic of Anesthesia, University of Duisburg-Essen, Essen, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Schäfer
authors.affiliation: Department of Research Immunology, Bavarian Nordic GmbH, Martinsried, Germany.
authors.forename: Hubertus
authors.initials: H
authors.lastname: Hochrein
authors.affiliation: Genome Informatics, Institute of Human Genetics, University of Duisburg-Essen, Essen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Rahmann
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.affiliation: Centre of Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Henneke
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Buer
authors.affiliation: Institute of Medical Microbiology, University of Duisburg-Essen, Essen, Germany carsten.kirschning@uk-essen.de.
authors.forename: Carsten J
authors.initials: CJ
authors.lastname: Kirschning
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004926:Escherichia coli / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D009843:Oligoribonucleotides; D012313:RNA / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D012329:RNA, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D000077278:RNA, Mitochondrial; D012336:RNA, Ribosomal, 16S; D013211:Staphylococcus aureus / Q000235:genetics / Q000276:immunology; D051200:Toll-Like Receptor 8 / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D009843:Oligoribonucleotides; D012329:RNA, Bacterial; D000077278:RNA, Mitochondrial; D012336:RNA, Ribosomal, 16S; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D012313:RNA
keywords: RNA; bacteria; human TLR8; mitochondrial; ribosomal