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

Hingley-Wilson SM, Connell D, Pollock K, Hsu T, Tchilian E, Sykes A, Grass L, Potiphar L, Bremang S, Kon OM, Jacobs WR, Lalvani A - Tuberculosis (Edinb) (2014)

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.

View Article: PubMed Central - PubMed

Affiliation: Tuberculosis Research Centre, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom. Electronic address: s.hingley-wilson@surrey.ac.uk.

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The production of fractalkine from THP-1 cells and human macrophages at 24 h post-infection is ESX1-dependent and does not cause necrosis. a) Fractalkine production as measured by a multiplex cytokine assay from THP-1 cells activated overnight with PMA and infected with an M.O.I. of 10:1 with H37Rv (Rv), H37Rv ΔESX1 (ΔESX1), complemented H37Rv ΔESX1 (C), untreated (U) or LPS treated (LPS, 10 ng/ml). b) Fractalkine production from THP-1 cells plus overnight IFN-γ (I) stimulation and infected as a. c) Fractalkine production from monocyte-derived macrophages from healthy controls and infected as a. d) Host cell necrosis, as measured by lactate dehydrogenase release, from human monocyte-derived macrophages at 72 h post-infection at an M.O.I. of 10:1. U = uninfected, FKN = treated with FKN, LPS = LPS treatment at 10 ng/ml, RV = H37Rv, RV/AF = Rv plus anti-fractalkine, + = Triton X-100 treated. Each experiment has been repeated three times, from three different healthy donors if primary cells. Statistical analyses were carried out using the Mann–Whitney non-parametric test.
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fig2: The production of fractalkine from THP-1 cells and human macrophages at 24 h post-infection is ESX1-dependent and does not cause necrosis. a) Fractalkine production as measured by a multiplex cytokine assay from THP-1 cells activated overnight with PMA and infected with an M.O.I. of 10:1 with H37Rv (Rv), H37Rv ΔESX1 (ΔESX1), complemented H37Rv ΔESX1 (C), untreated (U) or LPS treated (LPS, 10 ng/ml). b) Fractalkine production from THP-1 cells plus overnight IFN-γ (I) stimulation and infected as a. c) Fractalkine production from monocyte-derived macrophages from healthy controls and infected as a. d) Host cell necrosis, as measured by lactate dehydrogenase release, from human monocyte-derived macrophages at 72 h post-infection at an M.O.I. of 10:1. U = uninfected, FKN = treated with FKN, LPS = LPS treatment at 10 ng/ml, RV = H37Rv, RV/AF = Rv plus anti-fractalkine, + = Triton X-100 treated. Each experiment has been repeated three times, from three different healthy donors if primary cells. Statistical analyses were carried out using the Mann–Whitney non-parametric test.

Mentions: Secretion of all of the innate cytokines measured in response to infection with Mtb was similar to that with infection with the Mtb ΔESX1 mutant (Figure 1a–f), with the exception of the chemokine fractalkine (Figure 2a, P = 0.041). Therefore, uniquely among the panel of chemokines and cytokines evaluated, fractalkine induction at 24 h post-infection in Mtb-infected THP-1 cells is ESX1-mediated. This difference was also observed at 48 h post-infection (data not shown) but in both cases was only observed in resting macrophages, the suggested preferred interstitial niche of the tubercle bacillus [14] and was not seen in cells activated by the Th1 cytokine interferon-γ (IFN-γ; Figure 2b).


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

Hingley-Wilson SM, Connell D, Pollock K, Hsu T, Tchilian E, Sykes A, Grass L, Potiphar L, Bremang S, Kon OM, Jacobs WR, Lalvani A - Tuberculosis (Edinb) (2014)

The production of fractalkine from THP-1 cells and human macrophages at 24 h post-infection is ESX1-dependent and does not cause necrosis. a) Fractalkine production as measured by a multiplex cytokine assay from THP-1 cells activated overnight with PMA and infected with an M.O.I. of 10:1 with H37Rv (Rv), H37Rv ΔESX1 (ΔESX1), complemented H37Rv ΔESX1 (C), untreated (U) or LPS treated (LPS, 10 ng/ml). b) Fractalkine production from THP-1 cells plus overnight IFN-γ (I) stimulation and infected as a. c) Fractalkine production from monocyte-derived macrophages from healthy controls and infected as a. d) Host cell necrosis, as measured by lactate dehydrogenase release, from human monocyte-derived macrophages at 72 h post-infection at an M.O.I. of 10:1. U = uninfected, FKN = treated with FKN, LPS = LPS treatment at 10 ng/ml, RV = H37Rv, RV/AF = Rv plus anti-fractalkine, + = Triton X-100 treated. Each experiment has been repeated three times, from three different healthy donors if primary cells. Statistical analyses were carried out using the Mann–Whitney non-parametric test.
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Related In: Results  -  Collection

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fig2: The production of fractalkine from THP-1 cells and human macrophages at 24 h post-infection is ESX1-dependent and does not cause necrosis. a) Fractalkine production as measured by a multiplex cytokine assay from THP-1 cells activated overnight with PMA and infected with an M.O.I. of 10:1 with H37Rv (Rv), H37Rv ΔESX1 (ΔESX1), complemented H37Rv ΔESX1 (C), untreated (U) or LPS treated (LPS, 10 ng/ml). b) Fractalkine production from THP-1 cells plus overnight IFN-γ (I) stimulation and infected as a. c) Fractalkine production from monocyte-derived macrophages from healthy controls and infected as a. d) Host cell necrosis, as measured by lactate dehydrogenase release, from human monocyte-derived macrophages at 72 h post-infection at an M.O.I. of 10:1. U = uninfected, FKN = treated with FKN, LPS = LPS treatment at 10 ng/ml, RV = H37Rv, RV/AF = Rv plus anti-fractalkine, + = Triton X-100 treated. Each experiment has been repeated three times, from three different healthy donors if primary cells. Statistical analyses were carried out using the Mann–Whitney non-parametric test.
Mentions: Secretion of all of the innate cytokines measured in response to infection with Mtb was similar to that with infection with the Mtb ΔESX1 mutant (Figure 1a–f), with the exception of the chemokine fractalkine (Figure 2a, P = 0.041). Therefore, uniquely among the panel of chemokines and cytokines evaluated, fractalkine induction at 24 h post-infection in Mtb-infected THP-1 cells is ESX1-mediated. This difference was also observed at 48 h post-infection (data not shown) but in both cases was only observed in resting macrophages, the suggested preferred interstitial niche of the tubercle bacillus [14] and was not seen in cells activated by the Th1 cytokine interferon-γ (IFN-γ; Figure 2b).

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.

View Article: PubMed Central - PubMed

Affiliation: Tuberculosis Research Centre, Department of Respiratory Medicine, National Heart and Lung Institute, Imperial College London, London W2 1PG, United Kingdom. Electronic address: s.hingley-wilson@surrey.ac.uk.

Show MeSH
Related in: MedlinePlus