Systems Studies Uncover miR-146a as a Target in Leishmania major Infection Model

Abstract

Leishmaniasis, the second most neglected tropical disease, has been reported to affect approximately 12 million people worldwide. The causative protozoan parasite Leishmania has shown drug resistance to available chemotherapies, owing to which we need to look for better approaches to deal with the clinical situations. As per recent reports, several miRNAs have been found to be differentially expressed during Leishmania major infection in host macrophages. We aim to evaluate the impact of miRNA-mediated gene regulation on the key players of inflammation and macrophage dysfunction. The origin of Leishmania miRNAs and their processing is a questionable phenomenon as of yet. Through our study, we aim to provide a framework of their characterization. We amalgamate chemical systems biology and synthetic biology approaches to identify putative miRNA targets and unravel the complexity of host–pathogen gene regulatory networks.

Super enhancer-mediated transcription of miR146a-5p drives M2 polarization during Leishmania donovani infection

“…discovered that L . major exports miR146a-5p like elements in infected THP-1 cells, which in turn targets SMAD7, a mediator of TGFβ signaling network [ 22 ] . Such findings instigated us to explore mechanistic prominence of miR146a-5p in targeting another major immune-regulatory arm like TLR4 signaling mediators TRAF6 and IRAK1 and its effect upon macrophage polarization during L .…”

“…Additionally, miR181-5p and miR125a-5p were previously shown to have substantial role in inducing M2 polarization via targeting c/EBPα-KLF6 axis and KLF13 respectively [29,30].However, amongst all the M2 regulating miRNAs, miR146a-5p showed maximum enrichment during L. donovani infection. Recently, by chemical circuit-based and systems biology-based approaches, Nimsarkar et al discovered that L. major exports miR146a-5p like elements in infected THP-1 cells, which in turn targets SMAD7, a mediator of TGFβ signaling network [22]. Such findings instigated us to explore mechanistic prominence of miR146a-5p in targeting another major immune-regulatory arm like TLR4 signaling mediators TRAF6 and IRAK1 and its effect upon macrophage polarization during L. donovani infection.…”

“…Small-RNA sequencing earlier showed enrichment of miR146a-5pin L. major infected human PBMCs [17]. Moreover, the miRNA been shown to regulate macrophage polarization via TGFβ as well as Notch-pathway dependent manner [21,22]. Till date role of miR146a in macrophage polarization regulation has been explored in the light ofSMAD7-TRAF6-TGFβ pathway regulation [22].…”

“…Moreover, the miRNA been shown to regulate macrophage polarization via TGFβ as well as Notch-pathway dependent manner [21,22]. Till date role of miR146a in macrophage polarization regulation has been explored in the light ofSMAD7-TRAF6-TGFβ pathway regulation [22]. However, involvement of miR146a-5p mediated regulation of M2 polarization via targeting TRAF6-IRAK1-NF-κB axis during L. donovani infection is still poorly explored.…”

Activity of Anti-Microbial Peptides (AMPs) against Leishmania and Other Parasites: An Overview

“…After malaria, it is the most worrying parasitic illness worldwide [32]. About 0.7−1 million new cases of leishmaniasis are reported annually, generating around 20,000−30,000 deaths, according to WHO [33]. Leishmania parasites have a complex life cycle consisting of two stages: promastigote in the vector sandfly and amastigote in mammalian hosts.…”