Phagosomal RNA sensing through TLR8 controls susceptibility to tuberculosis.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-05-06 DOI:10.1016/j.celrep.2025.115657

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

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Abstract

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.

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通过TLR8检测吞噬体RNA控制结核病的易感性。

对结核分枝杆菌（Mtb）易感性的遗传决定因素仍然知之甚少，但可以提供有关感染的关键途径的见解，为宿主导向的治疗提供信息，并使个体和人群水平的风险分层成为可能。通过全基因组正向遗传筛选，我们确定toll样受体8 （TLR8）是Mtb细胞内杀伤的关键调节因子。TLR8的药理激活增强了巨噬细胞和小鼠体内感染对系统发育不同的耐药和耐药结核分枝杆菌临床分离株的杀伤作用。TLR8被胞外膜囊泡释放的吞噬体分枝杆菌RNA激活，增强异种吞噬依赖性结核分枝杆菌杀伤。我们发现TLR8变体M1V，在远东人群中常见，通过优先的信号依赖性转运到吞噬体，增强了Mtb的细胞内杀伤。因此，TLR8信号可能既调节对结核病的易感性，又提供新的药物靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.