{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Maserumule C"],"funding":["Grand Challenges","Cambridge Commonwealth Trust","NIHR Cambridge Biomedical Research Centre","Fondation Botnar","Wellcome Trust","Cystic Fibrosis Trust"],"pagination":["115657"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7618372"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["44(5)"],"pubmed_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"],"pubmed_title":["Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis."],"pmcid":["PMC7618372"],"funding_grant_id":["226602/Z/22/Z","107032","226602"],"pubmed_authors":["Gadwa J","Sanz J","Krishnananthasivam S","Prados-Rosales R","Kumar SS","Ordway D","Passemar C","Verma D","Andi K","Vongtongsalee K","Davila S","Hegyi K","Klapholz C","Weimann A","MacAry PA","Oh OSH","Dinan A","Vazquez-Iniesta L","Kendall E","Trelles A","Bertol J","Bryant J","Hibberd ML","Brown K","Floto RA","Maserumule C"],"additional_accession":[]},"is_claimable":false,"name":"Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis.","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 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.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 May","modification":"2026-05-18T03:17:12.897Z","creation":"2026-05-18T03:12:45.005Z"},"accession":"S-EPMC7618372","cross_references":{"pubmed":["40338743"],"doi":["10.1016/j.celrep.2025.115657"]}}