Abstract
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.
Highlights
As estimated by the 2016 global WHO report, Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) in humans, infects approximately 10 million people each year, making TB the second leading cause of death from an infectious disease worldwide [1].The success of Mtb principally relies on its ability to perfectly adapt to the host, by establishing latent infection and evading from the control driven by immune system
A cellular mechanism involved in intracellular pathogen elimination, is one of the pathways hijacked by Mtb to elude the control of dendritic cells (DC), major cellular effectors of immune response
It has become clear that Mtb infection alters cellular gene expression, and controls the level of small RNA molecules, namely microRNAs, which function as negative regulators of mRNA translation into protein
Summary
The success of Mtb principally relies on its ability to perfectly adapt to the host, by establishing latent infection and evading from the control driven by immune system. In this scenario, both innate and adaptive immune responses are required to control TB progression and pathogenesis [2]. The interaction of mycobacteria with antigen-presenting cells (APC) is a key feature in the pathogenesis of TB and the outcome of this interaction is pivotal in determining whether immunity or disease would ensue. Human and murine macrophages and dendritic cells (DC) were shown to be infected by mycobacteria and, in turn, to produce a specific immune response. As professional APC, DC display an extraordinary capacity to stimulate naïve T cells and initiate primary immune responses [3, 4]
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