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

ABSTRACT: Mycobacterium tuberculosis (Mtb) survives in macrophages by evading delivery to the lysosome and promoting the accumulation of lipid bodies, which serve as a bacterial source of nutrients. We found that by inducing the microRNA (miRNA) miR-33 and its passenger strand miR-33*, Mtb inhibited 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 promoted 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, which enhanced lipid catabolism and Mtb xenophagy. These data define a mammalian miRNA circuit used by Mtb to coordinately inhibit autophagy and reprogram host lipid metabolism to enable intracellular survival and persistence in the host.

SUBMITTER: Ouimet M

PROVIDER: S-EPMC4873392 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Ouimet Mireille M Koster Stefan S Sakowski Erik E Ramkhelawon Bhama B van Solingen Coen C Oldebeken Scott S Karunakaran Denuja D Portal-Celhay Cynthia C Sheedy Frederick J FJ Sheedy Frederick J FJ Ray Tathagat Dutta TD Cecchini Katharine K Zamore Philip D PD Rayner Katey J KJ Marcel Yves L YL Philips Jennifer A JA Moore Kathryn J KJ

Nature immunology 20160418 6

Mycobacterium tuberculosis (Mtb) survives in macrophages by evading delivery to the lysosome and promoting the accumulation of lipid bodies, which serve as a bacterial source of nutrients. We found that by inducing the microRNA (miRNA) miR-33 and its passenger strand miR-33*, Mtb inhibited 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 promoted autophagy f ...[more]

PMID: 27089382

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Project description:Autophagy is a primordial eukaryotic pathway, which provides the immune system with multiple mechanisms for the elimination of invading pathogens including Mycobacterium tuberculosis (Mtb). As a consequence, Mtb has evolved different strategies to hijack the autophagy process. Given the crucial role of human primary dendritic cells (DC) in host immunity control, we characterized Mtb-DC interplay by studying the contribution of cellular microRNAs (miRNAs) in the post-transcriptional regulation of autophagy related genes. From the expression profile of de-regulated miRNAs obtained in Mtb-infected human DC, we identified 7 miRNAs whose expression was previously found to be altered in specimens of TB patients. Among them, gene ontology analysis showed that miR-155, miR-155* and miR-146a target mRNAs with a significant enrichment in biological processes linked to autophagy. Interestingly, miR-155 was significantly stimulated by live and virulent Mtb and enriched in polysome-associated RNA fraction, where actively translated mRNAs reside. The putative pair interaction among the E2 conjugating enzyme involved in LC3-lipidation and autophagosome formation-ATG3-and miR-155 arose by target prediction analysis, was confirmed by both luciferase reporter assay and Atg3 immunoblotting analysis of miR-155-transfected DC, which showed also a consistent Atg3 protein and LC3 lipidated form reduction. Late in infection, when miR-155 expression peaked, both the level of Atg3 and the number of LC3 puncta per cell (autophagosomes) decreased dramatically. In accordance, miR-155 silencing rescued autophagosome number in Mtb infected DC and enhanced autolysosome fusion, thereby supporting a previously unidentified role of the miR-155 as inhibitor of ATG3 expression. Taken together, our findings suggest how Mtb can manipulate cellular miRNA expression to regulate Atg3 for its own survival, and highlight the importance to develop novel therapeutic strategies against tuberculosis that would boost autophagy.

Project description:Tuberculosis (TB), a bacterialinfectious disease caused by Mycobacterium tuberculosis (M.tb), which causes significant mortality in humans worldwide. Current treatment regimen involve the administration of multiple antibiotics over the course of several months that contributes to patient non-compliance leading to relapse and the development of drug-resistant M.tb (MDR and XDR) strains. Together, these facts highlight the need for the development of shorter TB treatment regimens. Host-directed therapy (HDT) is a new and emerging concept that aims to augment host immune response using drugs/compounds with or without adjunct antibiotics against M.tb infection. Autophagy is a natural catabolic mechanism of the cell that involves delivering the cytosolic constituents to the lysosomes for degradation and recycling the components; thereby maintaining the cellular and energy homoeostasis of a cell. However, over the past decade, an improved understanding of the role of autophagy in immunity has led to autophagy activation by using drugs or agents. This autophagy manipulation may represent a promising host-directed therapeutic strategy for human TB. However, current clinical knowledge on implementing autophagy activation by drugs or agents, as a stand-alone HDT or as an adjunct with antibiotics to treat human TB is insufficient. In recent years, many reports on high-throughput drug screening and measurement of autophagic flux by fluorescence, high-content microscopy, flow cytometry, microplate reader and immunoblotting have been published for the discovery of drugs that modulate autophagy. In this review, we discuss the commonly used chemical screening approaches in mammalian cells for the discovery of autophagy activating drugs against M.tbinfection. We also summarize the various autophagy-activating agents, both pre-clinical candidates and compounds approved for advanced clinical investigation during mycobacterial infection. Finally, we discuss the opportunities and challenges in using autophagy activation as HDT strategy to improve TB outcome and shorten treatment regimen.

Dataset Information

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

Publications

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

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