Bacterial RNA: An Underestimated Stimulus for Innate Immune Responses

Eigenbrod, Tatjana; Dalpke, Alexander H.

doi:10.4049/jimmunol.1500530

Cited by 87 publications

(73 citation statements)

References 83 publications

(124 reference statements)

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“…Upon submission of this study, four reports on Gram-positive bacterial RNA sensing by hTLR8 or on mTLR13 structure have been published and largely summarized [26][27][28][29][30]. Thus, S. aureus as well as Streptococcus pyogenes and Streptococcus agalactiae and Listeria monocytogenes total RNAs activate hTLR8 but not TLR7 [26,28].…”

Section: Perspective and Concluding Remarksmentioning

confidence: 98%

Human TLR 8 senses UR / URR motifs in bacterial and mitochondrial RNA

et al. 2015

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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.

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Section: Perspective and Concluding Remarksmentioning

confidence: 98%

Human TLR 8 senses UR / URR motifs in bacterial and mitochondrial RNA

et al. 2015

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“…For instance, TLR3 has been described to detect rhinovirus, and TLR7 recognizes the RNA‐viruses influenza virus, vesicular stomatitis virus, and Coxsackie B virus . Recent studies have shown that in particular human TLR8 is an important receptor for the detection of various pathogenic bacteria . Borrelia burgdorferi , the causative agent of Lyme disease, is recognized by TLR7 in human pDCs and induces secretion of type I and III IFNs .…”

Section: Role Of Rna‐sensing Tlrs In Detection Of Viruses Bacteria mentioning

confidence: 99%

“…TLR3 recognizes double‐stranded RNA (dsRNA) and utilizes the adaptor molecule TIR domain‐containing adapter‐inducing IFN‐β (TRIF, also known as TICAM1), while signal transduction of TLR7‐9 and TLR13 is dependent on myeloid differentiation primary response 88 (MyD88) . Human TLR7 and TLR8 both recognize single‐stranded RNA (ssRNA) and TLR9 is specific for unmethylated CpG DNA . The most recent identified NA‐sensing TLR is TLR13 which recognizes a specific sequence in bacterial 23S ribosomal RNA (rRNA) .…”

Section: Introductionmentioning

confidence: 99%

RNA is taking its Toll: Impact of RNA‐specific Toll‐like receptors on health and disease

Vierbuchen

Stein

Heine

2018

Allergy

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RNA-sensing Toll-like receptors (TLRs) are often described as antiviral receptors of the innate immune system. However, the past decade has shown that the function and relevance of these receptors are far more complex. They were found to be essential for the detection of various bacterial, archaeal, and eukaryotic microorganisms and facilitate the discrimination between dead and living microbes. The cytokine and interferon response profile that is triggered has the potential to improve the efficacy of next-generation vaccines and may prevent the development of asthma and allergy. Nevertheless, the ability to recognize foreign RNA comes with a cost as also damaged host cells can release nucleic acids that might induce an inappropriate immune response. Thus, it is not surprising that RNA-sensing TLRs play a key role in various autoimmune diseases. However, promising new inhibitors and antagonists are on the horizon to improve their treatment. K E Y W O R D Sarchaea, infection, RNA, TLR8, vaccines

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“…Of note, pDCs are very nearly the exclusive contributors to IFN secretion from PBMCs, which is why PBMC preparations are popular in measurements of TLR7 stimulation via ELISA-based quantification of IFN in the supernatant after exposure of PBMCs to stimulating agents. In contrast, TLR8 is found in monocytes where stimulation induces TNF (31). While RNA recognition of this system has long been described as specific for ssRNA (2), recent results suggest that this simplified review is in need for some refinement.…”

Section: Introductionmentioning

confidence: 99%

Bioconjugation of Small Molecules to RNA Impedes Its Recognition by Toll-Like Receptor 7

et al. 2017

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A fundamental mechanism of the innate immune system is the recognition, via extra- and intracellular pattern-recognition receptors, of pathogen-associated molecular patterns. A prominent example is represented by foreign nucleic acids, triggering the activation of several signaling pathways. Among these, the endosomal toll-like receptor 7 (TLR7) is known to be activated by single-stranded RNA (ssRNA), which can be specifically influenced through elements of sequence structure and posttranscriptional modifications. Furthermore, small molecules TLR7 agonists (smTLRa) are applied as boosting adjuvants in vaccination processes. In this context, covalent conjugations between adjuvant and vaccines have been reported to exhibit synergistic effects. Here, we describe a concept to chemically combine three therapeutic functions in one RNA bioconjugate. This consists in the simultaneous TLR7 stimulation by ssRNA and smTLRa as well as the therapeutic function of the RNA itself, e.g., as a vaccinating or knockdown agent. We have hence synthesized bioconjugates of mRNA and siRNA containing covalently attached smTLRa and tested their function in TLR7 stimulation. Strikingly, the bioconjugates displayed decreased rather than synergistically increased stimulation. The decrease was distinct from the antagonistic action of an siRNA bearing a Gm motive, as observed by direct comparison of the effects in the presence of otherwise stimulatory RNA. In summary, these investigations showed that TRL7 activation can be impeded by bioconjugation of small molecules to RNA.

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Bacterial RNA: An Underestimated Stimulus for Innate Immune Responses

Cited by 87 publications

References 83 publications

Human TLR 8 senses UR / URR motifs in bacterial and mitochondrial RNA

Human TLR 8 senses UR / URR motifs in bacterial and mitochondrial RNA

RNA is taking its Toll: Impact of RNA‐specific Toll‐like receptors on health and disease

Bioconjugation of Small Molecules to RNA Impedes Its Recognition by Toll-Like Receptor 7

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