Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis
Summary: 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 geno...
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| Language: | English |
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Elsevier
2025-05-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725004280 |
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| author | Charlotte Maserumule Charlotte Passemar Olivia S.H. Oh Kriztina Hegyi Karen Brown Aaron Weimann Adam Dinan Sonia Davila Catherine Klapholz Josephine Bryant Deepshikha Verma Jacob Gadwa Shivankari Krishnananthasivam Kridakorn Vongtongsalee Edward Kendall Andres Trelles Martin L. Hibberd Joaquín Sanz Jorge Bertol Lucia Vázquez-Iniesta Kaliappan Andi S. Siva Kumar Diane Ordway Rafael Prados-Rosales Paul A. MacAry R. Andres Floto |
| author_facet | Charlotte Maserumule Charlotte Passemar Olivia S.H. Oh Kriztina Hegyi Karen Brown Aaron Weimann Adam Dinan Sonia Davila Catherine Klapholz Josephine Bryant Deepshikha Verma Jacob Gadwa Shivankari Krishnananthasivam Kridakorn Vongtongsalee Edward Kendall Andres Trelles Martin L. Hibberd Joaquín Sanz Jorge Bertol Lucia Vázquez-Iniesta Kaliappan Andi S. Siva Kumar Diane Ordway Rafael Prados-Rosales Paul A. MacAry R. Andres Floto |
| author_sort | Charlotte Maserumule |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-fb80c0ab57bb4f6a826aa72d2edb5c95 |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-fb80c0ab57bb4f6a826aa72d2edb5c952025-08-20T02:27:24ZengElsevierCell Reports2211-12472025-05-0144511565710.1016/j.celrep.2025.115657Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosisCharlotte Maserumule0Charlotte Passemar1Olivia S.H. Oh2Kriztina Hegyi3Karen Brown4Aaron Weimann5Adam Dinan6Sonia Davila7Catherine Klapholz8Josephine Bryant9Deepshikha Verma10Jacob Gadwa11Shivankari Krishnananthasivam12Kridakorn Vongtongsalee13Edward Kendall14Andres Trelles15Martin L. Hibberd16Joaquín Sanz17Jorge Bertol18Lucia Vázquez-Iniesta19Kaliappan Andi20S. Siva Kumar21Diane Ordway22Rafael Prados-Rosales23Paul A. MacAry24R. Andres Floto25Molecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UKMolecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK; Victor Philip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UKDepartment of Microbiology, The Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeMolecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UKMolecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK; Victor Philip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UK; Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, UKMolecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK; Victor Philip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UK; Cambridge Centre for AI in Medicine, University of Cambridge, Cambridge, UKMolecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK; Victor Philip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UK; Cambridge Centre for AI in Medicine, University of Cambridge, Cambridge, UKInfectious Disease Group, Genome Institute of Singapore, Singapore, Singapore; SingHealth Duke-NUS Institute of Precision Medicine, SingHealth Duke-NUS Genomic, Medicine Centre, Cardiovascular and Metabolic Disorder Program, Duke-NUS Medical, School, Singapore, SingaporeMolecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UKMolecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK; Cambridge Centre for AI in Medicine, University of Cambridge, Cambridge, UKMycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USAMycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USADepartment of Microbiology, The Yong Loo Lin School of Medicine, National University of Singapore, Singapore, SingaporeMycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USAMycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USAMycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USAInfectious Disease Group, Genome Institute of Singapore, Singapore, Singapore; London School of Hygiene and Tropical Medicine, London, UKInstitute for Bio-computation and Physics of Complex Systems BIFI, Department of Theoretical Physics, University of Zaragoza, Zaragoza, SpainInstitute for Bio-computation and Physics of Complex Systems BIFI, Department of Theoretical Physics, University of Zaragoza, Zaragoza, SpainDepartment of Preventive Medicine, Public Health and Microbiology, School of Medicine, Universidad Autónoma de Madrid, Madrid, SpainICMR-National Institute for Research in Tuberculosis, Chennai, IndiaICMR-National Institute for Research in Tuberculosis, Chennai, IndiaMycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USADepartment of Preventive Medicine, Public Health and Microbiology, School of Medicine, Universidad Autónoma de Madrid, Madrid, SpainDepartment of Microbiology, The Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Corresponding authorMolecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK; Victor Philip Dahdaleh Heart & Lung Research Institute, University of Cambridge, Cambridge, UK; Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge, UK; Cambridge Centre for AI in Medicine, University of Cambridge, Cambridge, UK; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124725004280CP: Immunology |
| spellingShingle | Charlotte Maserumule Charlotte Passemar Olivia S.H. Oh Kriztina Hegyi Karen Brown Aaron Weimann Adam Dinan Sonia Davila Catherine Klapholz Josephine Bryant Deepshikha Verma Jacob Gadwa Shivankari Krishnananthasivam Kridakorn Vongtongsalee Edward Kendall Andres Trelles Martin L. Hibberd Joaquín Sanz Jorge Bertol Lucia Vázquez-Iniesta Kaliappan Andi S. Siva Kumar Diane Ordway Rafael Prados-Rosales Paul A. MacAry R. Andres Floto Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis Cell Reports CP: Immunology |
| title | Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis |
| title_full | Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis |
| title_fullStr | Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis |
| title_full_unstemmed | Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis |
| title_short | Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis |
| title_sort | phagosomal rna sensing through tlr8 controls susceptibility to tuberculosis |
| topic | CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725004280 |
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