The roles of microRNAs on tuberculosis infection: meaning or myth?

Abstract

The central proteins for protection against tuberculosis are attributed to interferon-γ, tumor necrosis factor-α, interleukin (IL)-6 and IL-1β, while IL-10 primarily suppresses anti-mycobacterial responses. Several studies found alteration of expression profile of genes involved in anti-mycobacterial responses in macrophages and natural killer (NK) cells from active and latent tuberculosis and from tuberculosis and healthy controls. This alteration of cellular composition might be regulated by microRNAs (miRNAs). Albeit only 1% of the genomic transcripts in mammalian cells encode miRNA, they are predicted to control the activity of more than 60% of all protein-coding genes and they have a huge influence in pathogenesis theory, diagnosis and treatment approach to some diseases. Several miRNAs have been found to regulate T cell differentiation and function and have critical role in regulating the innate function of macrophages, dendritic cells and NK cells. Here, we have reviewed the role of miRNAs implicated in tuberculosis infection, especially related to their new roles in the molecular pathology of tuberculosis immunology and as new targets for future tuberculosis diagnostics.

Keywords: Mycobacterium tuberculosis; Tuberculosis immunology; Tuberculosis infection; microRNA.

Figure 1

The roles of miRNAs in pathology tuberculosis infection. Several studies revealed evidence that Mycobacterium species infection in several cell types upregulated miR-99b, miR-144*, miR-29 and miR-125b. These miRNAs target several genes that are important in tuberculosis immunity. Upregulated of these miRNAs help Mycobacterial to survival inside host cells and enhance anti-tuberculosis immunity by inhibiting production of proinflammatory cytokines and inducing IL-10 through several mechanisms. Abbreviation: 3′UTR: 3′-untranslated region, Ago2: Argonaute 2, IFN-γ: Interferon-γ, IL-12: Interleukin 12, IL-1β: Interleukin 1β, IL-6: Interleukin 6, Jak-STAT: Janus kinase/signal transducers and activators of transcription, MAPK: mitogen-activated protein kinase, NF-κB: nuclear factor κ beta, TLR: Toll-like receptor, TNFRSF-4: tumor necrosis factor receptor superfamily, member 4, TNF-α: tumor necrosis factor-α.

Figure 2

The role of miR-155 on virulent (green) and avirulent (yellow) Mycobacterium species infection in macrophage. Avirulent Mycobacterium species infection upregulates of miR-155 by triggering the TLR2/PI3K/PKCδ/MAPK signaling pathways then recruit of NF-κB and c-ETS to miR-155 promoter. miR-155 induces apoptosis of infected macrophage by targeting PKI-α 3′UTR thus increases PKA signaling and finally activates of apoptotic effectors, caspase-3, cytochrome c translocation. miR-155 also increases TNF production by increasing TNF mRNA stability. To meet this role, miR-155 directly targeting SHIP1 3′UTR, a negative regulator of the PI3K/Akt pathway, a pathway involves in TNF biosynthesis and enhances MK2 phosphorylation which is a key molecule for TNF mRNA stability. Conflict results come from virulent Mycobacterium infections. Infection in murine macrophage induces miR-155 expression then attenuates the SHIP1 and Bach1 expressions therefore promote mycobacterium dormancy and survival in macrophages. Moreover, upregulation of miR-155 inhibits the expression IL-6 and cyclooxygenase-2. However, virulent Mycobacterium infection in human macrophage downregulates miR-155. Briefly, this condition decrease TNF production by decreasing TNF mRNA half time and decreases PI3K/Akt pathway. Abbreviation. 3′UTR: 3′ -untranslated region, Cox-2: cyclooxygenase-2, CREB: cyclic AMP response element binding protein, MAPK: mitogen-activated protein kinase, MK2: MAPK activated protein kinase 2, MSK1: mitogen and stress-activated protein kinase-1, NF-κB: nuclear factor κ beta, PI3K: phosphatidylinositol 3-kinase, PKCδ: protein kinase Cδ, PKI-α: protein kinase inhibitor alpha, SHIP1: SH2-containing inositol 5-phosphatase, TLR: Toll-like receptor. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)