ESX1-dependent fractalkine mediates chemotaxis and Mycobacterium tuberculosis infection in humans

Suzanne M. Hingley-Wilson (Lead / Corresponding author), David Connell, Katrina Pollock, Tsungda Hsu, Elma Tchilian, Anny Sykes, Lisa Grass, Lee Potiphar, Samuel Bremang, Onn Min Kon, William R. Jacobs, Ajit Lalvani

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    Abstract

    Mycobacterium tuberculosis-induced cellular aggregation is essential for granuloma formation and may assist establishment and early spread of M. tuberculosis infection. The M. tuberculosis ESX1 mutant, which has a non-functional type VII secretion system, induced significantly less production of the host macrophage-derived chemokine fractalkine (CX3CL1). Upon infection of human macrophages ESX1-dependent fractalkine production mediated selective recruitment of CD11b+ monocytic cells and increased infection of neighbouring cells consistent with early local spread of infection. Fractalkine levels were raised in vivo at tuberculous disease sites in humans and were significantly associated with increased CD11b+ monocytic cellular recruitment and extent of granulomatous disease. These findings suggest a novel fractalkine-dependent ESX1-mediated mechanism in early tuberculous disease pathogenesis in humans. Modulation of M. tuberculosis-mediated fractalkine induction may represent a potential treatment option in the future, perhaps allowing us to switch off a key mechanism required by the pathogen to spread between cells.

    Original languageEnglish
    Pages (from-to)262-270
    Number of pages9
    JournalTuberculosis
    Volume94
    Issue number3
    Early online date3 Feb 2014
    DOIs
    Publication statusPublished - May 2014

    Keywords

    • Animals
    • Bacterial Proteins/physiology
    • CD11 Antigens/metabolism
    • Cells, Cultured
    • Chemokine CX3CL1/metabolism
    • Chemotaxis/physiology
    • Humans
    • Macrophages/microbiology
    • Matrix Metalloproteinases/metabolism
    • Mice, Inbred BALB C
    • Monocytes/microbiology
    • Mycobacterium tuberculosis/pathogenicity
    • Tuberculosis/microbiology

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  • Cite this

    Hingley-Wilson, S. M., Connell, D., Pollock, K., Hsu, T., Tchilian, E., Sykes, A., Grass, L., Potiphar, L., Bremang, S., Kon, O. M., Jacobs, W. R., & Lalvani, A. (2014). ESX1-dependent fractalkine mediates chemotaxis and Mycobacterium tuberculosis infection in humans. Tuberculosis, 94(3), 262-270. https://doi.org/10.1016/j.tube.2014.01.004