Identification of a novel role of ESAT-6-dependent miR-155 induction during infection of macrophages with Mycobacterium tuberculosis.
Mycobacterium tuberculosis (M.tb.) replicates in host macrophages to cause tuberculosis. We have investigated the role of miRNAs in M.tb.-infected murine RAW264.7 cells and bone marrow-derived macrophages (BMDMs), focusing on miR-155, the most highly upregulated miRNA. We observed that miR-155 upregulation is directly linked to the attenuation of expression of BTB and CNC homology 1 (Bach1) and SH2-containing inositol 5'-phosphatase (SHIP1). Bach1 is a transcriptional repressor of haem oxygenase-1 (HO-1), whereas SHIP1 inhibits the activation of the serine/threonine kinase AKT. We hypothesize that M.tb.-induced miR-155 induction leads to repression of Bach1, which augments the expression of HO-1, a documented activator of the M.tb. dormancy regulon. SHIP1 repression facilitates AKT activation, which is required for M.tb. survival. In addition, M.tb.-induced miR-155 inhibits expression of cyclooxygenase-2 (Cox-2) and interleukin-6 (Il-6), two modulators of the innate immune response. Importantly, we observed that the virulence-associated secreted protein ESAT-6 plays a key role in miR-155 induction and its subsequent effects on Bach1 and SHIP1 repression. Inhibition of miR-155 hindered survival of M.tb. in RAW264.7 and in murine BMDMs. Thus, our results offer new insights into the role of miRNAs in modulation of the host innate immune response by M.tb. for its own benefit.
Department of Chemistry, Bose Institute, Kolkata, India.
Ranjeet
R
Kumar
Priyanka
P
Halder
Sanjaya K
SK
Sahu
Manish
M
Kumar
Mandavi
M
Kumari
Kuladip
K
Jana
Zhumur
Z
Ghosh
Pawan
P
Sharma
Manikuntala
M
Kundu
Joyoti
J
Basu
D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D057131:Immune Evasion; D000072181:Inositol Polyphosphate 5-Phosphatases; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D050296:Microbial Viability; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis
D000942:Antigens, Bacterial; C486316:Bach1 protein, mouse; D001426:Bacterial Proteins; D050976:Basic-Leucine Zipper Transcription Factors; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases