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.
Highlights
Tuberculosis (TB) is a global pandemic, killing more than any other infectious disease [1], and ongoing transmission in high incidence settings impedes control measures [2]
We have identified for the first time regulatory pathways which limit matrix metalloproteinases (MMPs)-1 production in human macrophages, including phosphoinositol-3 kinase (PI3K), AKT and mTORC1, and show that PI3K expression is reduced in pulmonary granulomas of patients with TB
The PI3K pathway has multiple subunits, and we studied the PI3Kδ subunit which is expressed in cells derived from the blood by specific inhibition with IC87114 (PI3Kδ, PI3Kγ and PI3Kβ = IC50 0.5, 29 and 75μM, respectively)
Summary
Tuberculosis (TB) is a global pandemic, killing more than any other infectious disease [1], and ongoing transmission in high incidence settings impedes control measures [2]. Mycobacterium tuberculosis (Mtb), the causative organism, must cause lung destruction to create highly infectious individuals with pulmonary cavities who drive the pandemic [3]. The precise role of MNK-mediated eIF4E phosphorylation is unclear, but is considered to differentially affect the translation of multiple mRNAs [12,13,14]. Expression of these intracellular signalling molecules can be regulated by microRNAs [15], and Mtb infection of macrophages can modulate this microRNA profile [16,17,18]
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