Abstract
Autophagy plays an important role in protecting the host against pathogens. Mycobacterium tuberculosis can suppress autophagy and then remain dormant and survive within the host for an extended period, which is responsible for latent tuberculosis infection (LTBI). Here, we explored the role of microRNAs (miRNAs) in LTBI. The miRNA profiles were explored using the next-generation sequencing approach, followed by quantitative reverse transcription-PCR validation. The biological function of candidate miRNA was evaluated using immunoblotting, immunofluorescence techniques, and enzyme-linked immunosorbent assay in an in vitro human TB granuloma model. An increased miR-889 expression was observed in patients with LTBI compared with that in patients without infection. The reporter assay identified tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) as the target of miR-889. Mycobacterial infection induced TWEAK upregulation in the early phase. TWEAK induced autophagy and promoted mycobacterial autophagosome maturation through activation of AMP-activated protein kinase (AMPK). Upon entry to LTBI status, elevated miR-889 levels were associated with TNF alpha (TNF-α) and granuloma formation/maintenance. MiR-889 inhibited autophagy via posttranscriptional suppression of TWEAK expression to maintain mycobacterial survival in granulomas. Adalimumab (anti-TNF-α monoclonal antibody) treatment reduced levels of both TNF-α and miR-889 and caused granuloma destruction and LTBI reactivation. The circulating miR-889 and TWEAK levels were correlated with LTBI and subsequently associated with anti-TNF-α-related LTBI reactivation in patients. We propose that miR-889 and TWEAK can act as targets that can be manipulated for antimycobacterial therapeutic purposes and act as candidate biomarkers for LTBI and LTBI reactivation, respectively.IMPORTANCE TB remains a leading cause of morbidity and mortality worldwide. Approximately one-quarter of the world's population has latent TB infection. TWEAK is a multiple-function cytokine and may be used as a target for the treatment of rheumatic diseases, cardiovascular diseases, and renal diseases. Here, we demonstrated a novel relationship between TWEAK and activation of the autophagic machinery which promotes antimycobacterial immunity. Additionally, TB infection is highly dynamic and determined by the interaction between the host and mycobacterium. We demonstrated a mechanism of fine-tuned balance between the mycobacterium and host for granuloma formation and/or maintenance in LTBI status. Once patients entered LTBI status, the upregulation of miR-889 was associated with TNF-α levels and granuloma formation to maintain mycobacterial survival. Adalimumab (a TNF-α inhibitor) reduced both TNF-α and miR-889 levels and caused LTBI reactivation and, thus, TWEAK enhancement. MiR-889 and TWEAK may become potential diagnostic biomarkers or therapeutic targets for LTBI and LTBI reactivation, respectively.
Highlights
Autophagy plays an important role in protecting the host against pathogens
Host responses in controlling the latent infection may include macrophage activation, maintenance of granuloma structure, and expression of IFN-␥, tumor necrosis factor (TNF)-␣, CD4 T cells, and CD8 T cells [21]
® mbio.asm.org we revealed a novel mechanism of fine-tuned balance between mycobacteria and the host for granuloma formation and/or maintenance in patients with the latent tuberculosis infection (LTBI) status
Summary
Autophagy plays an important role in protecting the host against pathogens. Mycobacterium tuberculosis can suppress autophagy and remain dormant and survive within the host for an extended period, which is responsible for latent tuberculosis infection (LTBI). Once patients entered LTBI status, the upregulation of miR-889 was associated with TNF-␣ levels and granuloma formation to maintain mycobacterial survival. Mycobacterium tuberculosis has developed a mechanism that prevents the autophagy of immune cells so that it can survive in host cells and remain dormant for a longer period, which is responsible for latent TB infection (LTBI) [2]. Accumulating validations demonstrate that miRNAs are regulators during mycobacterial infections and can be potential biomarkers for the diagnosis of TB diseases [13, 14]. Most of these miRNAs were involved in TB pathogenesis by targeting autophagy-related genes (ATGs) or regulating autophagic activity, and mycobacterial survival was maintained. The role of miRNAs in modulating host defenses in the LTBI period and their clinical relevance are unclear
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