Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis

Maserumule, Charlotte ; Passemar, Charlotte ; Oh, Olivia S.H. ; Hegyi, Kriztina ; Brown, Karen ; Weimann, Aaron ; Dinan, Adam ; Davila, Sonia ; Klapholz, Catherine ; Bryant, Josephine ; Verma, Deepshikha ; Gadwa, Jacob ; Krishnananthasivam, Shivankari ; Vongtongsalee, Kridakorn ; Kendall, Edward ; Trelles, Andres ; Hibberd, Martin L. ; Sanz, Joaquín (Universidad de Zaragoza) ; Bertol, Jorge ; Vázquez-Iniesta, Lucia ; Andi, Kaliappan ; Kumar, S. Siva ; Ordway, Diane ; Prados-Rosales, Rafael ; MacAry, Paul A. ; Floto, R. Andres

Resumen: 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.

Idioma: Inglés

DOI: 10.1016/j.celrep.2025.115657

Año: 2025

Publicado en: Cell Reports 44, 5 (2025), 115657 [21 pp.]
ISSN: 2211-1247

Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2019-110240RB-I00
Financiación: info:eu-repo/grantAgreement/ES/MICINN/PID2022-136611OB-I00

Tipo y forma: Article (Published version)

Área (Departamento): Área Física Teórica (Dpto. Física Teórica)