ESX1-dependent fractalkine mediates chemotaxis and Mycobacterium tuberculosis infection in humans.
Bottom Line: 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).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.
Affiliation: Tuberculosis Research Centre, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom. Electronic address: email@example.com.Show MeSH
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Mentions: Elucidation of the fundamental role of M. marinum-induced ESX-1-dependent MMP-9 secretion in zebrafish embryos  after we generated the above data prompted us to investigate ESX1-dependence of MMP-9 secretion in our human system. We assessed production of MMP-9 in THP-1 cells, both with and without IFN-γ, and in human MDMs and found no difference between Mtb H37Rv and the Mtb ΔESX1 mutant. This was also the case with cells activated with conditioned media from infected macrophages (Figure 3a–c). Although we observed substantial production of MMP9 in human alveolar epithelial cells (A549 cell line; Figure 3d) there was no ESX-1 mediated difference. The zebrafish immune system differs substantially from the human, so we studied several other MMPs (1, 2, 7 and 10) to see if an alternative MMP might be acting in the place of the zebrafish MMP9 and there was no observable ESX1-mediated difference in the MMPs 1, 2 7 or 10 (Supplementary Figure 1).
Affiliation: Tuberculosis Research Centre, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom. Electronic address: firstname.lastname@example.org.