title: 2'-O-Methylation within Bacterial RNA Acts as Suppressor of TLR7/TLR8 Activation in Human Innate Immune Cells.
abstract: Microbial RNA is an important stimulator of innate immune responses. Differences in posttranscriptional RNA modification profiles enable the immune system to discriminate between self and non-self nucleic acids. This principle may be exploited by certain bacteria to circumvent immune cell activation. In this regard, 2'-O-methylation of Escherichia coli tRNATyr at position 18 (Gm18) has recently been described to inhibit TLR7-mediated IFN-α production in human plasmacytoid dendritic cells (pDCs). Extending these findings, we now demonstrate that Gm18 also potently inhibits TLR7-independent human monocyte activation by RNA derived from a variety of bacterial strains. The half minimal inhibitory concentration values were similar to those found for IFN-α inhibition in pDCs. Mechanistically, 2'-O-methylated RNA impaired upstream signalling events, including MAP kinase and NFx03BA;B activation. Our results suggest that antagonizing effects of Gm18-modified RNA are due to competition with stimulatory RNA for receptor binding. The antagonistic effect was specific for RNA because the small molecule TLR7/8 agonist R848 was not inhibited. Despite the striking phenotype in human cells, 2'-O-methylated RNA did not interfere with TLR13 activation by bacterial 23S rRNA in murine DC and BMDM. Thus, we identify here Gm18 in E. coli tRNA(Tyr) as a universal suppressor of innate immune activation in the human but not the murine system.
authors.affiliation: Department of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Rimbach
authors.forename: Steffen
authors.initials: S
authors.lastname: Kaiser
authors.forename: Mark
authors.initials: M
authors.lastname: Helm
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Dalpke
authors.forename: Tatjana
authors.initials: T
authors.lastname: Eigenbrod
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000382:microbiology; D004926:Escherichia coli / Q000235:genetics / Q000276:immunology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007165:Immunosuppression Therapy; D016898:Interferon-alpha / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008815:Mice, Inbred Strains; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology; D016328:NF-kappa B / Q000378:metabolism; D012329:RNA, Bacterial / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013045:Species Specificity; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology*; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000276:immunology*
chemical_list: D016898:Interferon-alpha; D016328:NF-kappa B; D012329:RNA, Bacterial; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D048049:Extracellular Signal-Regulated MAP Kinases
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