Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis
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.
Authors
- Andres Trelles
- Martin L. Hibberd (ORCID: https://orcid.org/0000-0001-8587-1849)
- Charlotte Passemar (ORCID: https://orcid.org/0000-0003-4990-0758)
- Catherine Klapholz
- Joaquín Sanz (ORCID: https://orcid.org/0000-0002-2980-9685)
- Kridakorn Vongtongsalee (ORCID: https://orcid.org/0009-0005-8522-0620)
- Paul A. MacAry (ORCID: https://orcid.org/0000-0002-1139-8996)
- Adam M. Dinan (ORCID: https://orcid.org/0000-0003-2812-1616)
- Sonia Dávila (ORCID: https://orcid.org/0000-0001-7466-959X)
- Kaliappan Andi
- Kriztina Hegyi
- Edward C. Kendall (ORCID: https://orcid.org/0000-0002-8562-0617)
- Aaron Weimann (ORCID: https://orcid.org/0000-0003-4597-2471)
- Charlotte Maserumule (ORCID: https://orcid.org/0000-0002-0771-6031)
- Josephine M. Bryant (ORCID: https://orcid.org/0000-0002-0149-5768)
- Shivankari Krishnananthasivam (ORCID: https://orcid.org/0000-0001-7141-0590)
- Jacob Gadwa (ORCID: https://orcid.org/0000-0003-0560-2337)
- Diane Ordway (ORCID: https://orcid.org/0000-0003-0003-326X)
- Olivia S H Oh
- R. Andrés Floto (ORCID: https://orcid.org/0000-0002-2188-5659)
- Rafael Prados‐Rosales (ORCID: https://orcid.org/0000-0001-5964-0166)
- Karen Brown (ORCID: https://orcid.org/0000-0002-0387-5318)
- Jorge Bertol
- Lucía Vázquez-Iniesta
- Deepshikha Verma (ORCID: https://orcid.org/0000-0002-8549-6409)
- S Siva Kumar
Institutions
- SingHealth (SG)
- National University of Singapore (SG)
- MRC Laboratory of Molecular Biology (GB)
- University of Cambridge (GB)
- Universidad de Zaragoza (ES)
- Royal Papworth Hospital (GB)
- SingHealth Duke-NUS Academic Medical Centre (SG)
- National Institute of Research in Tuberculosis (IN)
- Universidad Autónoma de Madrid (ES)
- Genome Institute of Singapore (SG)
- Colorado State University (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-05-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115657
- Primary Topic
- Immune Response and Inflammation
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Bill and Melinda Gates Foundation
- Wellcome Trust
- Francis Crick Institute
- National Institute for Health and Care Research
- Cystic Fibrosis Trust
- Cambridge Commonwealth Trust
- Ministerio de Ciencia e Innovación
- Fondation Botnar
- National Institutes of Health
- Medical Research Council
- NIHR Cambridge Biomedical Research Centre