Mycobacterium tuberculosis induces the miR-33 locus to reprogram autophagy and host lipid metabolism

Abstract

Mycobacterium tuberculosis (Mtb) survives within macrophages by evading delivery to the lysosome and promoting the accumulation of lipid bodies, which serve as a bacterial source of nutrients. Here we show that by inducing miR-33 and its passenger strand miR-33*, Mtb inhibits integrated pathways involved in autophagy, lysosomal function and fatty acid oxidation to support bacterial replication. Silencing of miR-33 and miR-33* by genetic or pharmacological means promotes autophagy flux through derepression of key autophagy effectors such as ATG5, ATG12, LC3B and LAMP1 and AMPK-dependent activation of the transcription factors FOXO3 and TFEB, enhancing lipid catabolism and Mtb xenophagy. These data define a mammalian miRNA circuit utilized by Mtb to coordinately inhibit autophagy and reprogram host lipid metabolism to enable intracellular survival and persistence in the host.

PPAR-α Activation Mediates Innate Host Defense through Induction of TFEB and Lipid Catabolism

“…In addition, lipid-laden mycobacteria exhibit a drugresistance and dormancy-like phenotype, characteristics associated with latent infection (57). A recent study reported that M. tuberculosis-induced miR-33/33* inhibited FAO and enhanced lipid-body formation in macrophages (23). Importantly, we found that PPAR-a activation promoted lipid catabolism and upregulated the expression of genes involved in FAO in M. tuberculosisinfected macrophages.…”

“…Previous studies also reported that TFEB plays a crucial role in the link between lipophagy and FAO and in the transcriptional regulation of genes involved in several steps of lipid degradation (16). Moreover, silencing of miR-33/33* decreased lipid accumulation and induced lipolysis, which were correlated with increased xenophagy and antimicrobial responses against M. tuberculosis in macrophages (23). Thus, these data suggest that PPAR-a activation induces lipid catabolism to enhance destruction of the foamy refuges of mycobacteria in host cells.…”

“…Ppara +/+ and Ppara 2/2 BMDM were infected with M. tuberculosis-or BCG-ERFP and stimulated with GW7647 or Wy14643 for 24 h. For neutral lipids were stained using BODIPY 493/503, as previously described (23). Cells were fixed in 4% (v) paraformaldehyde and neutral lipids were stained using 5 mg/ml of BODIPY 493/503 (D-3922; Molecular Probes) for 30 min at RT.…”

Macrophages

“…miR-33 controls M2 polarization through the alteration of mitochondrial function 18 and key metabolic (AMP-activated protein kinase) 19 and autophagy effectors, 20,21 of high relevance to atherosclerosis and associated cardiometabolic diseases. Long-term inhibition of miR-33 (subcutaneous anti-miR) in C57/Bl6 mice fed a high-fat diet upregulates hepatic ABCA1 (but not SREBP1), promotes whole-body oxidative metabolism and M2 polarization in adipose tissue, and decreases circulating triglyceride levels, although it does not improve insulin resistance.…”

Mycobacteria and Autophagy: Many Questions and Few Answers

“…Another study reported that Mtb regulates miR-155 through an ESAT6-dependent manner to overcome its elimination and promote infection in macrophages (Kumar et al, 2012). Mtb also induces miR-33 and its passenger strand to inhibit integrated pathways involved in autophagy and reprogram host lipid metabolism to enable intracellular survival (Ouimet et al, 2016). Mtb blocks the autophagic machinery by blocking phagosome maturation through secretion of the macromolecules, PtpA and SapM.…”