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

Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology
Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology
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.
1553-7366
1-25
Brace, Patience
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Tezera, Liku B.
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Bielecka, Magdalena K.
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Mellows, Toby
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Garay, Diana
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Tian, Shuye
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Rand, Lucinda
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Green, Justin
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Jogai, Sanjay
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Steele, Andrew
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Millar, Timothy M.
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Sanchez-Elsner, Tilman
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Friedland, Jon S.
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Proud, Christopher G.
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Elkington, Paul T.
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Brace, Patience
1884d9b7-6d4c-4c5d-bf9d-b7b1848a0d0a
Tezera, Liku B.
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Bielecka, Magdalena K.
90391ea3-aa1f-4104-a893-568c138718a2
Mellows, Toby
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Garay, Diana
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Tian, Shuye
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Rand, Lucinda
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Green, Justin
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Jogai, Sanjay
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Steele, Andrew
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Millar, Timothy M.
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Sanchez-Elsner, Tilman
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Friedland, Jon S.
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Proud, Christopher G.
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Elkington, Paul T.
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Brace, Patience, Tezera, Liku B., Bielecka, Magdalena K., Mellows, Toby, Garay, Diana, Tian, Shuye, Rand, Lucinda, Green, Justin, Jogai, Sanjay, Steele, Andrew, Millar, Timothy M., Sanchez-Elsner, Tilman, Friedland, Jon S., Proud, Christopher G. and Elkington, Paul T. (2017) Mycobacterium tuberculosis subverts negative regulatory pathways in human macrophages to drive immunopathology. PLoS Pathogens, 13 (6), 1-25. (doi:10.1371/journal.ppat.1006367).

Record type: Article

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.

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Accepted/In Press date: 17 April 2017
e-pub ahead of print date: 1 June 2017
Published date: 1 June 2017
Organisations: Cancer Sciences, Centre for Biological Sciences, Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 408449
URI: https://eprints.soton.ac.uk/id/eprint/408449
ISSN: 1553-7366
PURE UUID: e88bc315-18a7-4e8c-a3d7-ea68c3ff971c
ORCID for Liku B. Tezera: ORCID iD orcid.org/0000-0002-7898-6709
ORCID for Diana Garay: ORCID iD orcid.org/0000-0002-9450-8504
ORCID for Andrew Steele: ORCID iD orcid.org/0000-0003-0667-1596
ORCID for Timothy M. Millar: ORCID iD orcid.org/0000-0002-4539-2445
ORCID for Paul T. Elkington: ORCID iD orcid.org/0000-0003-0390-0613

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Date deposited: 20 May 2017 04:04
Last modified: 10 Dec 2019 06:04

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