4 years ago

<i>Mycobacterium tuberculosis</i> subverts negative regulatory pathways in human macrophages to drive immunopathology

Timothy M. Millar, Magdalena K. Bielecka, Toby Mellows, Sanjay Jogai, Shuye Tian, Patience T. Brace, Andrew J. Steele, Liku B. Tezera, Justin Green, Christopher G. Proud, Diana Garay, Lucinda Rand, Tilman Sanchez-Elsner, Jon S. Friedland, Paul T. Elkington

by Patience T. Brace, Liku B. Tezera, Magdalena K. Bielecka, Toby Mellows, Diana Garay, Shuye Tian, Lucinda Rand, Justin Green, Sanjay Jogai, Andrew J. Steele, Timothy M. Millar, Tilman Sanchez-Elsner, Jon S. Friedland, Christopher G. Proud, Paul T. Elkington

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.

Publisher URL: http://journals.plos.org/plosone/article

DOI: 10.1371/journal.ppat.1006367

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.