Fundamental role of spatial positioning of Mycobacterium tuberculosis in mycobacterial survival in macrophages.

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-10-23 DOI:10.1038/s41467-025-64404-z

Shivani Sahu,Navin Baid,Deepali Aggarwal,Ankita Sharma,Manisha Gun,Sahanawaz Molla,Anunay Sinha,Ambey Prasad Dwivedi,Amit Tuli,Mahak Sharma,Sanjeev Khosla,Varadharajan Sundaramurthy,Ashwani Kumar

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Abstract

Mycobacterium tuberculosis is a model intracellular pathogen. The spatial-localization of M. tuberculosis inside macrophages is poorly defined. Here, we determine the spatial-localization of M. tuberculosis inside macrophages with reference to the nucleus. Few M. tuberculosis cells are perinuclear, while most are peripheral. Perinuclear M. tuberculosis are transported to lysosomes, have low Adenosine Triphosphate/Adenosine Diphosphate, are non-replicating, and tolerate front-line anti-tubercular medicines. M. tuberculosis pathogenicity determines its spatial location. Virulent M. tuberculosis strains are peripheral. However, avirulent M. tuberculosis strains or attenuated deletion mutants are transported to lysosomes in the perinuclear area. Early Secreted Antigenic Target-6 and Culture Filtrate Protein-10 play a critical role in inhibiting mycobacterial transport to the perinuclear space. Induction of centripetal transport of pathogenic M. tuberculosis-laden cargoes to perinuclear region enhances M. tuberculosis's delivery to the lysosomes and reduces mycobacterial growth. Interferon-γ directs M. tuberculosis to lysosomes by modulating their perinuclear localization. Interferon-γ upregulates Transmembrane protein 55B and JNK-interacting protein 4 via transcription factor EB. Increased transmembrane protein 55B and JNK-interacting protein 4 levels tether M. tuberculosis-laden cargoes to the dynein motor, causing their perinuclear delivery to lysosomes. These findings shed light on how mycobacterial metabolism, reproduction, and drug susceptibility are connected to virulence-guided spatial localization.

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巨噬细胞中结核分枝杆菌空间定位在分枝杆菌存活中的基础作用。

结核分枝杆菌是一种典型的细胞内病原体。巨噬细胞内结核分枝杆菌的空间定位尚不明确。在这里，我们根据细胞核确定了巨噬细胞内结核分枝杆菌的空间定位。很少有结核分枝杆菌细胞是核周的，而大多数是外周的。核周结核分枝杆菌被转运到溶酶体，具有低三磷酸腺苷/二磷酸腺苷，不复制，耐受一线抗结核药物。结核分枝杆菌的致病性决定了它的空间位置。毒力强的结核分枝杆菌属外周菌株。然而，无毒结核分枝杆菌菌株或减毒缺失突变体被转运到核周区域的溶酶体。早期分泌抗原靶蛋白-6和培养滤液蛋白-10在抑制分枝杆菌转运到核周间隙中起关键作用。诱导致病性结核分枝杆菌装载的货物向核周区域的向心运输增强了结核分枝杆菌对溶酶体的递送并减少了分枝杆菌的生长。干扰素-γ通过调节溶酶体的核周定位来引导结核分枝杆菌到达溶酶体。干扰素γ通过转录因子EB上调跨膜蛋白55B和jnk相互作用蛋白4。增加的跨膜蛋白55B和jnk相互作用蛋白4水平将携带结核分枝杆菌的货物拴在动力蛋白马达上，导致它们在核周围传递到溶酶体。这些发现揭示了分枝杆菌的代谢、繁殖和药物敏感性如何与毒力引导的空间定位相关联。

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

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.