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Abstract
Our current knowledge of mycobacterial infections in humans has progressively increased over the past few decades. The infection of Mycobacterium tuberculosis causes tuberculosis (TB) disease, which has reasoned for excessive morbidity and mortality worldwide, and has become a foremost issue of health problem globally. Mycobacterium leprae, another member of the family Mycobacteriaceae, is responsible for causing a chronic disease known as leprosy that mainly affects mucosa of the upper respiratory tract, skin, peripheral nerves, and eyes. Ample amount of existing data suggests that pathogenic mycobacteria have skilled in utilizing different mechanisms to escape or offset the host immune responses. They hijack the machinery of immune cells through the modulation of microRNAs (miRs), which regulate gene expression and immune responses of the host. Evidence shows that miRs have now gained considerable attention in the research, owing to their involvement in a broad range of inflammatory processes that are further implicated in the pathogenesis of several diseases. However, the knowledge of functions of miRs during mycobacterial infections remains limited. This review summarises recent findings of differential expression of miRs, which are used to good advantage by mycobacteria in offsetting host immune responses generated against them.
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Figure 1.
Regulation of apoptotic signaling pathways through miRs by M. tuberculosis. Diagrammatic representation of miRs and their target genes, which alter the canonical apoptotic pathways of immune cells, and assist in M. tuberculosis survival. In the extrinsic apoptotic pathway, TNFα binds to its receptors (TNFR1/4) and triggers its trimerization, which recruits TRADD, an adaptor molecule that allows binding of TRAF-2 and IAP to the receptor complex. RIP1, a kinase then binds TNFR1 through TRADD association. IAP proteins are responsible for RIP1 ubiquitination, and in their absence, RIP1 cannot be ubiquitinated. Non-ubiquitinated RIP1 can form a cytosolic complex with the caspase-8, leading to induction of apoptosis. The binding of TRAF-2 to the receptor complex stimulates the JNK pathway, which is a proapoptotic pathway. JNK can promote the release of Smac, from mitochondria, which inhibits TRAF2/IAP complex formation, and relieves the inhibition of caspase-8, thereby triggering caspase activation. JNK also participates in intrinsic apoptotic pathway, as after activation, JNK translocates to the mitochondria and phosphorylates BH3-only family of Bcl-2 proteins, which antagonize the anti-apoptotic activity of Bcl-2 or Bcl-Xl proteins. Further, JNK stimulates the release cyt C from mitochondrial inner membrane through BID-Bax dependent mechanism and promotes apoptosomes formation from released cyt C, caspase-9, and Apaf-1. The apoptosomes initiates caspase-9-dependent caspase cascade. In FasR pathway, a FasL binds to FasR and induces the recruitment of FADD followed by activation of procaspase-8, which further activates caspase-3 (the executioner) causing apoptosis. Caspase-8 also cleaves BID, a BH3 domain-containing protein of the BCL-2, which triggers intrinsic apoptosis and amplifies the signal from the extrinsic pathway. The expression of another member of BH3 only protein is increased by FOXO1 and FOXO3, which initiates the Bax/Bak-dependent apoptotic pathway.
Figure 2.
Immunomodulation of macrophages through miRs. A schematic diagram represents different miRs and their target genes, which allows M. tuberculosis to mitigate the immune response through modulation of TLR and IFN-γ pathway. The ligation of mycobacterial ligands to TLRs leads to the interaction of MyD88 with IRAK4 and IRAK1. IRAK4 auto-phosphorylates and activates IRAK1. This promotes the activation of TRAF6, which further activates TAK1. TAK1 gives rise to canonical IKK complex by phosphorylating IKKα and IKKβ, which phosphorylates components of the transcription factor NF-κ B such as Iκ Bα, p50, and p65. TAK1-mediated activation of NF-κ B transcription factors drives the production of pro-inflammatory cytokines such as IL-12 and TNF-α. In another pathway, IFN-γ acts as a principal mediator of macrophage activation, which modulates pro-inflammatory cytokine production and induces production of anti-inflammatory molecules. Upon ligand binding, oligomerization and transphosphorylation of IFN-γ receptors (IFNR1 and IFNR2) activate JAK1 and JAK2, which creates a docking site for STAT1. STAT1 homodimerizes upon phosphorylation (P) in an antiparallel configuration, forming a complex γ-activated factor, which translocates to the nucleus and binds to the γ-activated site, located at the promoters of primary response genes, increasing their transcription, like IL-1Ra and IL-18BP. SOCS proteins negatively regulate the IFN-γ pathway by inhibiting JAKs and STAT1 phosphorylation.
Table 1.
Regulation of host miRs during M. tuberculosis infections
Table 2.
miR-mediated modulation of host immune response during M. bovis and other mycobacterial infections
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