Cell Reports (May 2025)
Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis
- 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
Affiliations
- Charlotte Maserumule
- Molecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK
- Charlotte Passemar
- Molecular 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
- Olivia S.H. Oh
- Department of Microbiology, The Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Kriztina Hegyi
- Molecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK
- Karen Brown
- Molecular 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
- Aaron Weimann
- Molecular 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, UK
- Adam Dinan
- Molecular 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, UK
- Sonia Davila
- Infectious 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, Singapore
- Catherine Klapholz
- Molecular Immunity Unit, University of Cambridge Department of Medicine, MRC-Laboratory of Molecular Biology, Cambridge, UK
- Josephine Bryant
- Molecular 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, UK
- Deepshikha Verma
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
- Jacob Gadwa
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
- Shivankari Krishnananthasivam
- Department of Microbiology, The Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Kridakorn Vongtongsalee
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
- Edward Kendall
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
- Andres Trelles
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
- Martin L. Hibberd
- Infectious Disease Group, Genome Institute of Singapore, Singapore, Singapore; London School of Hygiene and Tropical Medicine, London, UK
- Joaquín Sanz
- Institute for Bio-computation and Physics of Complex Systems BIFI, Department of Theoretical Physics, University of Zaragoza, Zaragoza, Spain
- Jorge Bertol
- Institute for Bio-computation and Physics of Complex Systems BIFI, Department of Theoretical Physics, University of Zaragoza, Zaragoza, Spain
- Lucia Vázquez-Iniesta
- Department of Preventive Medicine, Public Health and Microbiology, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
- Kaliappan Andi
- ICMR-National Institute for Research in Tuberculosis, Chennai, India
- S. Siva Kumar
- ICMR-National Institute for Research in Tuberculosis, Chennai, India
- Diane Ordway
- Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA
- Rafael Prados-Rosales
- Department of Preventive Medicine, Public Health and Microbiology, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
- Paul A. MacAry
- Department of Microbiology, The Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Corresponding author
- R. Andres Floto
- Molecular 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 author
- Journal volume & issue
-
Vol. 44,
no. 5
p. 115657
Abstract
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.
