| Autor: |
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, Rafael Prados-Rosales, Kaliappan Andi, S Siva Kumar, Diane Ordway, Paul A MacAry, R. Andres Floto |
| Rok vydání: |
2022 |
| Popis: |
Genetic determinants of susceptibility to Mycobacterium tuberculosis (Mtb) are 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 the Toll-like Receptor 8 (TLR8), as a key regulator of intracellular killing of Mtb. Pharmacological TLR8 activation enhances 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 signalling may therefore both regulate susceptibility to tuberculosis and provide novel drug targets.Single sentence summaryRNA released from Mycobacterium tuberculosis in the macrophage phagosome is sensed by the pattern recognition receptor TLR8 controlling host susceptibility to tuberculosis and revealing a druggable pathway for host-directed therapy. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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