Mycobacterium smegmatis But Not Mycobacterium avium subsp. hominissuis Causes Increased Expression of the Long Non-Coding RNA MEG3 in THP-1-Derived Human Macrophages and Associated Decrease of TGF-β

Abstract

Pathogenic mycobacteria are able to persist intracellularly in macrophages, whereas non-pathogenic mycobacteria are effectively combated and eliminated after their phagocytosis. It is known that TGF-β plays an important role in this context. Infection with pathogenic mycobacteria such as Mycobacterium tuberculosis or M. avium leads to production of active TGF-β, which blocks the ability of IFN-γ and TNF-α to inhibit intracellular replication. On the other hand, it is known that the long non-coding RNA (lncRNA) maternally expressed 3 (MEG3) is involved in the regulation of TGF-β. In this study, we show how the infection of THP-1-derived human macrophages with the saprophytic M. smegmatis but not with the facultatively pathogenic M. avium subsp. hominissuis leads to increased MEG3 expression. This is associated with the downregulation of DNA methyltransferases (DNMT) 1 and 3b, which are known to regulate MEG3 expression via promoter hypermethylation. Consequently, we observe a significant downregulation of TGF-β in M. smegmatis-infected macrophages but not in M. avium subsp. hominissuis pointing to lncRNAs as novel mediators of host cell response during mycobacterial infections.

Long Non-Coding RNA FGD5-AS1 Induced by Chlamydia trachomatis Infection Inhibits Apoptosis via Wnt/β-Catenin Signaling Pathway

“…LncRNAs have been shown to regulate DNA methylation and histone modification to change chromatin status, thereby affecting transcription during bacterial infection ( Wen et al., 2020a ). Mycobacterium smegmatis upregulated the expression of MEG3 to inhibit promoter hypermethylation, repressing the expression of TGF-β by forming RNA-DNA triplex structure ( Sharbati et al., 2019 ). Similar to Mycobacterium , Ct is an intracellular microbial pathogen.…”

Long noncoding RNAs in bacterial infection

“…Knockdown of MEG3 fostered the induction of autophagy and promoted clearance of M. bovis (Pawar, Hanisch, Palma Vera, Einspanier, & Sharbati, 2016a). Interestingly, different from M. bovis infection, MEG3 is upregulated in human THP1-derived macrophages upon challenge with M. smegmatis, which is considered nonpathogenic, but not with M. avum, which is a facultative pathogen (Sharbati et al, 2019). Thus, MEG3 might play different roles in response to different mycobacterial species.…”

Identification and characterization of novel infection associated transcripts in macrophages

“…Non coding response dynamics have helped uncover novel facets of host – pathogen interactions in several bacterial pathogens (Gomez et al 2013; Wang et al 2015; Roy et al 2018; Yan et al 2018). Not surprisingly, Mtb infection of macrophages induces several of the non-coding transcripts with functional relevance in activating innate immune functions as well as modulation of these responses by the pathogen (Yang et al 2016; Huang et al 2018; Sharbati et al 2019). Clinically relevant lncRNAs have recently been identified as putative biomarkers for TB patients (Chen et al 2017; Li et al 2017; Wu et al 2020).…”