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

Author

Listed:
  • Shivani Sahu

    (CSIR-Institute of Microbial Technology)

  • Navin Baid

    (CSIR-Institute of Microbial Technology)

  • Deepali Aggarwal

    (CSIR-Institute of Microbial Technology
    Academy of Scientific and Innovative Research)

  • Ankita Sharma

    (CSIR-Institute of Microbial Technology
    Academy of Scientific and Innovative Research)

  • Manisha Gun

    (CSIR-Institute of Microbial Technology)

  • Sahanawaz Molla

    (Tata Institute of Fundamental Research)

  • Anunay Sinha

    (CSIR-Institute of Microbial Technology
    Center for DNA Fingerprinting and Diagnostics)

  • Ambey Prasad Dwivedi

    (CSIR-Institute of Microbial Technology
    Center for DNA Fingerprinting and Diagnostics)

  • Amit Tuli

    (CSIR-Institute of Microbial Technology
    Academy of Scientific and Innovative Research)

  • Mahak Sharma

    (Indian Institute of Science Education and Research)

  • Sanjeev Khosla

    (CSIR-Institute of Microbial Technology
    Academy of Scientific and Innovative Research
    Center for DNA Fingerprinting and Diagnostics)

  • Varadharajan Sundaramurthy

    (Tata Institute of Fundamental Research)

  • Ashwani Kumar

    (CSIR-Institute of Microbial Technology
    Academy of Scientific and Innovative Research)

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.

Suggested Citation

  • Shivani Sahu & Navin Baid & Deepali Aggarwal & Ankita Sharma & Manisha Gun & Sahanawaz Molla & Anunay Sinha & Ambey Prasad Dwivedi & Amit Tuli & Mahak Sharma & Sanjeev Khosla & Varadharajan Sundaramur, 2025. "Fundamental role of spatial positioning of Mycobacterium tuberculosis in mycobacterial survival in macrophages," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64404-z
    DOI: 10.1038/s41467-025-64404-z
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    References listed on IDEAS

    as
    1. Ari J. Firestone & Joshua S. Weinger & Maria Maldonado & Kari Barlan & Lance D. Langston & Michael O’Donnell & Vladimir I. Gelfand & Tarun M. Kapoor & James K. Chen, 2012. "Small-molecule inhibitors of the AAA+ ATPase motor cytoplasmic dynein," Nature, Nature, vol. 484(7392), pages 125-129, April.
    2. Gaurav Kumar & Prateek Chawla & Neha Dhiman & Sanya Chadha & Sheetal Sharma & Kanupriya Sethi & Mahak Sharma & Amit Tuli, 2022. "RUFY3 links Arl8b and JIP4-Dynein complex to regulate lysosome size and positioning," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
    3. Rose Willett & José A. Martina & James P. Zewe & Rachel Wills & Gerald R. V. Hammond & Rosa Puertollano, 2017. "TFEB regulates lysosomal positioning by modulating TMEM55B expression and JIP4 recruitment to lysosomes," Nature Communications, Nature, vol. 8(1), pages 1-17, December.
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