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Review
. 2022 Oct 27:12:1009901.
doi: 10.3389/fcimb.2022.1009901. eCollection 2022.

microRNAs associated with the pathogenesis and their role in regulating various signaling pathways during Mycobacterium tuberculosis infection

Kusuma Sai Davuluri  1 , Devendra S Chauhan  1
Affiliations
Review

microRNAs associated with the pathogenesis and their role in regulating various signaling pathways during Mycobacterium tuberculosis infection

Kusuma Sai Davuluri et al. Front Cell Infect Microbiol. .

Abstract

Despite more than a decade of active study, tuberculosis (TB) remains a serious health concern across the world, and it is still the biggest cause of mortality in the human population. Pathogenic bacteria recognize host-induced responses and adapt to those hostile circumstances. This high level of adaptability necessitates a strong regulation of bacterial metabolic characteristics. Furthermore, the immune reponse of the host virulence factors such as host invasion, colonization, and survival must be properly coordinated by the pathogen. This can only be accomplished by close synchronization of gene expression. Understanding the molecular characteristics of mycobacterial pathogenesis in order to discover therapies that prevent or resolve illness relies on the bacterial capacity to adjust its metabolism and replication in response to various environmental cues as necessary. An extensive literature details the transcriptional alterations of host in response to in vitro environmental stressors, macrophage infection, and human illness. Various studies have recently revealed the finding of several microRNAs (miRNAs) that are believed to play an important role in the regulatory networks responsible for adaptability and virulence in Mycobacterium tuberculosis. We highlighted the growing data on the existence and quantity of several forms of miRNAs in the pathogenesis of M. tuberculosis, considered their possible relevance to disease etiology, and discussed how the miRNA-based signaling pathways regulate bacterial virulence factors.

Keywords: anti-TB treatment; miRNA; pathogenesis; signaling pathways; tuberculosis.

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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
Maturation of microRNA (miRNA). RNA polymerase II or III modifies the primary miRNA into the cap structure through polyadenylation. The Drosha complex crops the miRNA into a hairpin-shaped pre-miRNA during the initial processing of pri-miRNA in the nucleus. Immature miRNA is exported to the cytoplasm by the exportin-5/Ran-GTP complex for Dicer processing. One of the miRNA duplex strands forms miRNA-RISC, which engages on the target mRNA to mediate gene silencing via translational repression or mRNA degradation/deadenylation (detailed in Figure 1 ). The epigenetic modifications during the transcription process render the miRNA unable to carry out its normal functions. Messenger ribonucleic acid (mRNA); micro ribonucleic acid (miRNA); deoxyribo nucleic acid (DNA); RNA-induced silencing complex (RISAC).
Figure 2
Figure 2
Major miRNAs that regulate apoptosis effectors are shown in the diagram in the yellow box. FasR, Fas Receptor; FADD, Fas-associated death domain protein. miRNAs regulate the major cascades of autophagy. The action of miRNAs involved in the regulation of key members of autophagy cascades; repression/activation of mRNA are shown in the nucleus. mTORC1 induces and regulates the autophagy by miRNAs. AMPK-mTORC1 lies at the heart of regulation of autophagy by integrating numerous stimuli and pathways into a signal for the starting point of autophagy. In addition, ER stress and ROS regulate autophagy independently of the AMPK-mTORC1 pathway. In TNF-α-induced necroptosis, the engagement of TNFR1 recruits Complex I (composed of TRADD, TRAF2). This complex promotes the NF-κB activation and promotes cell survival and inhibits apoptosis. When growth factor receptors are activated, the class I PI3K complex and a small GTPase, Ras, are activated, which activate the PI3K-PKD1-AKT and Ras-Raf-1-MEK1/2-ERK1/2 pathways, respectively. Both AKT and ERK1/2 phosphorylate and inhibit tuberous sclerosis complex, thereby stabilizing Ras homolog, which activates mTORC1, resulting in autophagy inhibition. JNK1-mediated Bcl-2 phosphorylation reduces the binding activity of Bcl-2 and Bcl-xL to initiate autophagy, which promotes cell survival. TLR signaling and miRNAs form a complex network. TLR recruits adaptor proteins and activates downstream signaling cascades that activate the NF-κB signaling pathway and the MAPK signaling pathway in response to specific microbial recognition. This activation causes inflammatory mediators and miRNA genes to be expressed.
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