{"doi":"10.1016/j.celrep.2025.115657","title":"Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis","abstract":"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 Toll-like receptor 8 (TLR8) as a key regulator of intracellular killing of Mtb. Pharmacological TLR8 activation enhances the 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 signaling may, therefore, both regulate susceptibility to tuberculosis and provide novel drug targets.","journal":"Cell Reports","year":2025,"id":533647,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":989132,"name":"Charlotte Passemar","orcid":"0000-0003-4990-0758","position":1,"is_corresponding":false},{"id":989721,"name":"Olivia S H Oh","orcid":null,"position":2,"is_corresponding":false},{"id":989722,"name":"Kriztina Hegyi","orcid":null,"position":3,"is_corresponding":false},{"id":503199,"name":"Karen Brown","orcid":"0000-0002-0387-5318","position":4,"is_corresponding":false},{"id":989133,"name":"Aaron Weimann","orcid":"0000-0003-4597-2471","position":5,"is_corresponding":false},{"id":457693,"name":"Adam M. 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