MicroRNA-199a Inhibits Cellular Autophagy and Downregulates IFN-β Expression by Targeting TBK1 in Mycobacterium bovis Infected Cells.

Jie Wang,Srinand Sreevatsan,Qiang Li,Ruichao Yue,Tariq Hussain,Xin Sun,Lei Xu,Yi Liao,Nan Wang,Jiao Yao,Xiangmei Zhou,Yinjuan Song,Deming Zhao

doi:10.3389/fcimb.2018.00238

Abstract

The mechanism by which microRNAs (miRNAs) modulate innate immunity and autophagy has not been fully elucidated in Mycobacterium bovis (M. bovis) infections. In this study, we identified that miR-199a inhibited key innate immune responses and autophagy in murine macrophages infected with M. bovis. Using ex vivo and in vitro approaches we show that the expression of miR-199a was significantly increased during M. bovis infection. Furthermore, miR-199a suppressed autophagy and interferon-β (IFN-β) production by directly targeting TANK-binding kinase 1 (TBK1) mRNA in both J774a.1 and BMDM cells. Upregulation of miR-199a or TBK1 silencing (siTBK1) inhibited maturation of autophagosomes and increased M. bovis survival. Our results demonstrate that, by targeting of TBK1, miR-199a modulates innate immune responses and promote the intracellular survival and growth of M. bovis.

Highlights

Mycobacterium bovis is a causative agent of tuberculosis in multiple species of animals, including cattle
Blocking of type I IFN receptor subunit IFNα/β receptor 1 (IFNAR1) by using monoclonal antibodies MAR1-5A3 (Biolegend) resulted in a decreased bacterial load of M. bovis in macrophages (Figures 6D,E). These findings shows that TANK-binding kinase 1 (TBK1) is necessary for the regulation of autophagy and the elimination of M. bovis from infected macrophages and dominate IFN-β role in the survival of M. bovis
Study reported that M. bovis infection upregulate the expression of miR-146a and miR-146b in alveolar macrophages

Summary

Introduction

Mycobacterium bovis is a causative agent of tuberculosis in multiple species of animals, including cattle. It can cause disease in humans with lesions undistinguishable from those caused by M. tuberculosis. Micro-RNAs (miRNAs) are non-coding single-stranded RNAs with a length of about 22 nucleotides, which regulates gene expression by initiating degradation of mRNAs or by inhibiting protein translation (Ambros et al, 2003; Friedman et al, 2009). Recent research has demonstrated that miRNAs have an important role in immune regulation in infectious and some autoimmune diseases (Desvignes et al, 2012; Khan et al, 2013). Several other studies have clearly established the role of miRNAs in regulation of the immune response during M. tuberculosis infection (Maudet et al, 2014; Mehta and Baltimore, 2016). It is reported that inflammatory signaling pathways are likely regulated by mycobacteria through differential expression of miRNAs (Junger, 2011; Ma et al, 2011)

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Conclusion