Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis

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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Main Authors: 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
Format: Article
Language:English
Published: Elsevier 2025-05-01
Series:Cell Reports
Subjects:
CP: Immunology
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124725004280
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Summary: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.
ISSN:2211-1247

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