ESAT-6 modulates Calcimycin-induced autophagy through microRNA-30a in mycobacteria infected macrophages - 18/07/19
Highlights |
• | Calcimycin-induced autophagy was inhibited by PPD 3 compared to PPD 10. |
• | Autophagy inhibition by PPD 3 increased intracellular survival of mycobacteria. |
• | rESAT-6 in PPD 3 fraction inhibits autophagy and enhances mycobacterial growth. |
• | rESAT-6 regulated Calcimycin-induced autophagy by modulating miR-30a expression. |
• | Inhibition of anti-autophagic response by miR-30a-3p kills intracellular bacteria. |
Abstract |
Objective |
Mycobacterium tuberculosis (M. tb) has a sumptuous repertoire of effector molecules to counter host defenses. Some of these antigens inhibit autophagy but the exact mechanism of this inhibition is poorly understood.
Methods |
Purified protein derivative (PPD) was fractionated using 10 (PPD 10, antigenic molecular weight > 10 kDa) and 3 (PPD 3, mol. weight > 3 kDa) kDa cutters. Effect of these fractions on Calcimycin-induced autophagy and intracellular mycobacterial viability was then studied using different experimental approaches.
Result |
We found significant downregulation of autophagy by PPD 3 pre-treatment in Calcimycin-treated dTHP-1 cells compared to PPD 10. This reduction in autophagy also corroborated with the enhanced survival of mycobacteria in macrophages. We demonstrate that recombinant early secreted antigenic target 6 (rESAT-6) is responsible to inhibit Calcimycin-induced autophagy and enhance intracellular survival of mycobacteria. We also show that pre-treatment with rESAT-6 upregulates microRNA (miR)-30a-3p expression and vis-a-vis downregulates miR-30a-5p expression in Calcimycin-treated dTHP-1 cells. Transfection studies with either miR-30a-3p inhibitor or miR-30a-5p mimic clearly elucidated the opposing roles of miR-30a-3p and miR-30a-5p in rESAT-6 mediated mycobacterial survival through autophagy inhibition.
Conclusion |
Taken together, our result evidently highlights that rESAT-6 enhances intracellular survival of mycobacteria by modulating miR-30a-3p and miR-30a-5p expression.
Le texte complet de cet article est disponible en PDF.Keywords : Autophagy, Calcimycin, ESAT-6, Human macrophages, micro-RNA, Tuberculosis
Abbreviations : M. bovis BCG, M. tb, M. smegmatis, TB, dTHP-1, PPD, MDR, XDR, rESAT-6, miR, ROI, RNI, Eis, ManLAM, PtpA, ESX-1, CFP-10, Atg, LC3, PMA, 3-MA, Baf-A1, MDC, qRT-PCR, mRFP, EGFP, HDT
Plan
Vol 79 - N° 2
P. 139-152 - août 2019 Retour au numéro
Article précédent
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