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Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis

ABSTRACT: RNA released from Mycobacterium tuberculosis in the macrophage phagosome is sensed by the pattern recognition receptor TLR8 controlling host susceptibility to tuberculosis and revealing a druggable pathway for host-directed therapy

PROVIDER: PRJEB62758 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR11512178.fastq.gz	Fastqsanger.gz
	ERR11512179.fastq.gz	Fastqsanger.gz
	ERR11512180.fastq.gz	Fastqsanger.gz
	ERR11512181.fastq.gz	Fastqsanger.gz
	ERR11512182.fastq.gz	Fastqsanger.gz

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Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis

Project description:Genetic determinants of susceptibility to Mycobacterium tuberculosis (Mtb) remain poorly understood but could provide insights into critical pathways involved in infection, informing host-directed therapies and enabling risk stratification at individual and population levels. Through a genome-wide forward genetic screen, we identify the Toll-like Receptor 8 (TLR8), as a key regulator of intracellular killing of Mtb. Pharmacological TLR8 activation enhances killing of phylogenetically diverse clinical isolates of drug-susceptible and multidrug-resistant Mtb by macrophages and during in vivo infection in mice. TLR8 is activated by phagosomal mycobacterial RNA released by extracellular membrane vesicles, and enhances xenophagy-dependent Mtb killing. We find that the TLR8 variant, M1V, common in far eastern populations, enhances intracellular killing of Mtb through preferential signal-dependent trafficking to phagosomes. TLR8 signalling may therefore both regulate susceptibility to tuberculosis and provide novel drug targets.

2025-02-05 | GSE288494 | GEO

Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis

Project description:Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis

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Bacterial RNA sensing by TLR8 requires RNase 6 processing and is inhibited by RNA 2’O-methylation

Project description:Mechanistic studies have revealed that TLR8 senses single-stranded RNA (ssRNA) fragments, processed via synergistic cleavage by ribonucleases (RNase) T2 and RNase A family members. Processing by these RNases releases uridines and purine-terminated residues resulting in TLR8 activation. Monocytes show high expression of RNase 6, yet this RNase has not been analyzed for its physiological contribution to recognition of bacterial RNA by TLR8. Herein, we characterized molecular RNase 6 cleavage mechanisms. BLaER1 RNASE6-/- cells showed a dampened TLR8-dependent response upon stimulation with isolated bacterial RNA (bRNA) but also upon infection with live whole bacteria. Pretreatment of bacterial RNA with recombinant RNase 6 generated fragments that induced stimulation in RNASE6 knockout cells. 2’O-RNA methyl modification, when introduced at the first uridine in the UA dinucleotide, impaired upstream processing by RNase 6 and dampened TLR8 stimulation. In summary, this data shows that RNase 6 plays a critical role in the processing of bacterial RNA by generating uridine-terminated breakdown products that ultimately activate TLR8.

2024-09-12 | PXD053881 | Pride

STING is essential for TLR8 induced IFN

Project description:The innate immune system is equipped with multiple receptors to detect microbial nucleic acids and induce type I interferon (IFN) to restrict viral replication. When dysregulated these receptor pathways induce inflammation in response to host nucleic acids and promote development and persistence of autoimmune diseases like Systemic Lupus Erythematosus (SLE). IFN production is regulated by the Interferon Regulatory Factor (IRF) transcription factor family of proteins that function downstream of several innate immune receptors such as Toll-like receptors (TLRs) and Stimulator of Interferon Genes (STING). Although both TLRs and STING activate the same downstream molecules, the pathway by which TLRs and STING activate IFN response are thought to be independent. Here we show that STING plays a previously undescribed role in human TLR8 signaling. Stimulation with the TLR8 ligands induced IFN secretion in primary human monocytes, and inhibition of STING reduced IFN secretion from primary monocytes from 8 healthy donors. We demonstrate that TLR8-induced IRF activity was reduced by STING inhibitors. Moreover, TLR8-induced IRF activity was blocked by inhibition or loss of IKKε, but not TBK1. Bulk RNA transcriptomic analysis supported a model where TLR8 induces transcriptional responses associated with SLE that can be downregulated by inhibition of STING. These data demonstrate that STING is required for full TLR8-to-IRF signaling and provide evidence for a new framework of crosstalk between cytosolic and endosomal innate immune receptors, which could be leveraged to treat IFN driven autoimmune diseases.

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RNA Sequencing of intra-phagosomal Mtb populations

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2019-09-13 | GSE123267 | GEO

Reversal of human regulatory T cell suppression throgh TLR8 signaling

Project description:Analyses of gene alterations of human Treg cells treated with or without TLR8 ligand using the Illumina whole-genome Human HT-12 BeadChips. The study will provide important information for the molecular signature changes during the reversal of human Treg suppression mediated by activation of TLR8 signaling.

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Distinct regulation of gene promoters and enhancers by CXCL4 and TLR8 in human CD14+ monocytes

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Quantitative Analysis of CXCL4 and TLR8 signaling crosstalk in human primary monocytes by RNA-Seq

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