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Review
. 2021 May 19:12:664787.
doi: 10.3389/fimmu.2021.664787. eCollection 2021.

The Roles of Host Noncoding RNAs in Mycobacterium tuberculosis Infection

Li Wei  1 , Kai Liu  2 , Qingzhi Jia  1 , Hui Zhang  3 , Qingli Bie  1   4 , Bin Zhang  1   4
Affiliations
Review

The Roles of Host Noncoding RNAs in Mycobacterium tuberculosis Infection

Li Wei et al. Front Immunol. .

Abstract

Tuberculosis remains a major health problem. Mycobacterium tuberculosis, the causative agent of tuberculosis, can replicate and persist in host cells. Noncoding RNAs (ncRNAs) widely participate in various biological processes, including Mycobacterium tuberculosis infection, and play critical roles in gene regulation. In this review, we summarize the latest reports on ncRNAs (microRNAs, piRNAs, circRNAs and lncRNAs) that regulate the host response against Mycobacterium tuberculosis infection. In the context of host-Mycobacterium tuberculosis interactions, a broad and in-depth understanding of host ncRNA regulatory mechanisms may lead to potential clinical prospects for tuberculosis diagnosis and the development of new anti-tuberculosis therapies.

Keywords: Mycobacterium tuberculosis (M. tuberculosis); circRNA; immune response; lncRNA; miRNA; piRNA.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
A brief summary of miRNA regulation of signaling pathways during M. tuberculosis infection. A schematic diagram represents different miRNAs and their target genes. MiR-708-5p and miR-1178 negatively regulates the level of TLR4 in macrophages. MiR-27b are induced by TLR2/MyD88/NF-κB pathway. MiR-125a and miR146a negatively regulate the NF-κB pathway by directly targeting TRAF6. MiR-132 and miR-26a down-regulate the transcriptional coactivator p300 (a molecule involved in IFN-γ signaling), miR-Let-7f targets A20, a feedback inhibitor of the NF-κB pathway. MiR-99b inhibit the activation of NF-κB, miR-196b-5p activate STAT3 signaling pathway via targeting negative regulators SOCS3. formula image Direct stimulatory modification; formula image Direct inhibitory modification.
Figure 2
Figure 2
Strategy of non-coding RNA regulating apoptosis pathway in M. tuberculosis infected cells. (A) MiR-155 and miR223 inhibit apoptosis by targeting FOXO3, miR-1281 inhibited apoptosis by targeting cyclophilin-d, miRNA-143 and miRNA-365 inhibit apoptosis by differentially targeting c-Maf, Bach-1, and Elmo-1. MiR-20a-5p negatively modulating Bim expression in a JNK2-dependent manner. MiR-125b-5p target DRAM2 to promot apoptosis, miR-325-3p targets LNX1 (the E3 ubiquitin ligase of NEK6), leading to abnormal accumulation of NEK6, which in turn activates the STAT3 signaling pathway. At the same time, potential ceRNAs are also flagged here. lincRNA-EPS inhibited apoptosis and enhanced autophagy by activating the JNK/MAPK signaling pathway. PCED1B-AS1 can directly bind to miR-155 to reduce the rate of apoptosis. LncRNA MEG3 can control miR-145-5p expression and regulate macrophage proliferation. The mechanism of action of ceRNA needs to be further studied and verified. (B) The apoptotic cells present antigen to DCs to trigger T-cell immunity. MiR-381-3p mediate the reduction of CD1c expression, thereby inhibiting T cell immune responses to M. tuberculosis. MiR-21 promotes the apoptosis of DCs by targeting Bcl-2, and inhibits IL-12 production by targeting IL-12p35, weakening the T-cell response to M. tuberculosis. formula image Direct stimulatory modification; formula image Direct inhibitory modification; formula image Tentative stimulatory modification; formula image Tentative inhibitory modification.
Figure 3
Figure 3
Infection by M. tuberculosis leads to alterations of miRNA expression in host cells, which regulate multiple steps of autophagy. MiR-26a facilitates upregulation of the KLF4, that favor the increased expression of Mcl-1 which in turn inhibits autophagosome formation miRNA-17-5p inhibits autophagy by inhibiting Mcl-1 and by binding to Beclin-1 to targe Mcl-1. MiR-33 inhibit autophagic flux by targeting lysosomal pathway transcription factors (FOXO3 and TFEB), activators (AMPK) and multiple effectors (ATG5, ATG12, LC3B and LAMP1). MiR-30a, miR-125a-3p and miR-144-5p respectively targeting Beclin-1, UVRAG and DRAM2. MiR-129-3p inhibit phagosome formation by targeting Atg4b. MiR-27a directly targets the Ca2+ transporter Cacna2d3 to inhibit autophagy. CircTRAPPC6B antagonized the ability of miR-874-3p to inhibit ATG16L1 expression, thereby activating and increasing autophagy. formula image Direct stimulatory modification; formula image Direct inhibitory modification; formula image Tentative stimulatory modification; formula image Tentative inhibitory modification.
Figure 4
Figure 4
1.A brief summary of circRNA and LncRNA regulation of signaling pathways during M. tuberculosis infection. Hsa_circ_101128 may be involved in the pathogenesis of active TB by negatively regulating let-7a and may be involved in the MAPK and PI3K-AKT pathways. Hsa_circ_001937 potential miRNA target is miR-26b, which participate in the inflammatory response by modulating the NF-κB pathway by targeting PTEN. CircAGFG1 can enhance autophagy is achieved by targeting miRNA1257 to regulate Notch signal in the macrophages infected by M. tuberculosis. 2.Models involving lncRNAs that target the host immune system of M. tuberculosis. M. tuberculosis infection leads to upregulation of lncRNA-CD244 in CD8+ T cells, which interacts with chromatin modifying enzyme EZH2, and lncRNA-CD244 acts as an epigenetic regulator of IFN-γ and TNF-α in CD8+ T cells and suppresses their expression to modulate the TB immune response of CD8+ T cells. formula image Direct stimulatory modification; formula image Direct inhibitory modification; formula image Tentative stimulatory modification; formula image Tentative inhibitory modification.
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