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Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology.

Brace, PT; Tezera, LB; Bielecka, MK; Mellows, T; Garay, D; Tian, S; Rand, L; Green, J; Jogai, S; Steele, AJ; et al. Brace, PT; Tezera, LB; Bielecka, MK; Mellows, T; Garay, D; Tian, S; Rand, L; Green, J; Jogai, S; Steele, AJ; Millar, TM; Sanchez-Elsner, T; Friedland, JS; Proud, CG; Elkington, PT (2017) Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology. PLoS Pathog, 13 (6). e1006367. ISSN 1553-7374 https://doi.org/10.1371/journal.ppat.1006367
SGUL Authors: Friedland, Jonathan Samuel

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Abstract

Tuberculosis remains a global pandemic and drives lung matrix destruction to transmit. Whilst pathways driving inflammatory responses in macrophages have been relatively well described, negative regulatory pathways are less well defined. We hypothesised that Mycobacterium tuberculosis (Mtb) specifically targets negative regulatory pathways to augment immunopathology. Inhibition of signalling through the PI3K/AKT/mTORC1 pathway increased matrix metalloproteinase-1 (MMP-1) gene expression and secretion, a collagenase central to TB pathogenesis, and multiple pro-inflammatory cytokines. In patients with confirmed pulmonary TB, PI3Kδ expression was absent within granulomas. Furthermore, Mtb infection suppressed PI3Kδ gene expression in macrophages. Interestingly, inhibition of the MNK pathway, downstream of pro-inflammatory p38 and ERK MAPKs, also increased MMP-1 secretion, whilst suppressing secretion of TH1 cytokines. Cross-talk between the PI3K and MNK pathways was demonstrated at the level of eIF4E phosphorylation. Mtb globally suppressed the MMP-inhibitory pathways in macrophages, reducing levels of mRNAs encoding PI3Kδ, mTORC-1 and MNK-1 via upregulation of miRNAs. Therefore, Mtb disrupts negative regulatory pathways at multiple levels in macrophages to drive a tissue-destructive phenotype that facilitates transmission.

Item Type: Article
Additional Information: © 2017 Brace et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Animals, Humans, Macrophages, Matrix Metalloproteinase 1, Mechanistic Target of Rapamycin Complex 1, Mice, Multiprotein Complexes, Mycobacterium tuberculosis, Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases, Tuberculosis, Pulmonary, Macrophages, Animals, Humans, Mice, Mycobacterium tuberculosis, Tuberculosis, Pulmonary, Multiprotein Complexes, Matrix Metalloproteinase 1, Phosphatidylinositol 3-Kinases, TOR Serine-Threonine Kinases, Mechanistic Target of Rapamycin Complex 1, Science & Technology, Life Sciences & Biomedicine, Microbiology, Parasitology, Virology, KINASE-INTERACTING KINASES, MATRIX METALLOPROTEINASE-1, PULMONARY TUBERCULOSIS, TRANSLATIONAL CONTROL, CELLULAR-METABOLISM, HOST, DISEASE, CELLS, PHOSPHORYLATION, INTERFERON, 0605 Microbiology, 1107 Immunology, 1108 Medical Microbiology, Virology
Journal or Publication Title: PLoS Pathog
ISSN: 1553-7374
Language: eng
Dates:
DateEvent
1 June 2017Published
19 April 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
MR/N006631/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
R33 AI102239NIAID NIH HHSUNSPECIFIED
PubMed ID: 28570642
Web of Science ID: WOS:000404511700011
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/110622
Publisher's version: https://doi.org/10.1371/journal.ppat.1006367

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