Highlighting the interplay of microRNAs from <i>Leishmania</i> parasites and infected-host cells

Rashidi, Sajad; Mansouri, Reza; Ali‐Hassanzadeh, Mohammad; Ghani, Esmaeel; Barazesh, Afshin; Karimazar, Mohammadreza; Nguewa, Paul; Silva, Eugenio Antonio Carrera

doi:10.1017/s0031182021001177

Cited by 12 publications

(8 citation statements)

References 150 publications

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“…In the present study, we examined miRNA expression in L. infantum infection to identify signatures likely associated with the pathogenic process. Few studies have evaluated the participation of miRNAs during Leishmania infection ( Lemaire et al., 2013 ; Muxel et al., 2017 ; Muxel et al., 2018 ; Fernandes et al., 2019 ; Paul et al., 2020 ; Rashidi et al., 2021 ; Souza et al., 2021 ). We compared miRNAs in plasma of patients with VL caused by L. infantum and in human monocyte-derived THP-1 cells infected in vitro with L. infantum .…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, miRNAs have been shown to play a critical role in developing functional immune responses ( Liu and Abraham, 2013 ). miRNAs have been implicated in various aspects of immunity to viruses, bacteria, and protozoan parasites, including Trypanosoma , Toxoplasma , Plasmodium , and Leishmania ( Chandan et al., 2019 ; Acuna et al., 2020 ; Rashidi et al., 2021 ). miRNAs have been considered as targets for therapeutic strategies, and since some miRNAs are considered stable in plasma and other biological fluids and are resistant to environmental conditions, they are also attractive as biomarkers of disease or therapeutic response ( Sohel, 2016 ; Takahashi et al., 2019 ; Souza et al., 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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miR-548d-3p Is Up-Regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages

Ramos-Sanchez

Reis

Souza

et al. 2022

Front. Cell. Infect. Microbiol.

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Visceral leishmaniasis caused by Leishmania (Leishmania) infantum in Latin America progress with hepatosplenomegaly, pancytopenia, hypergammaglobulinemia, and weight loss and maybe lethal mainly in untreated cases. miRNAs are important regulators of immune and inflammatory gene expression, but their mechanisms of action and their relationship to pathogenesis in leishmaniasis are not well understood. In the present study, we sought to quantify changes in miRNAs associated with immune and inflammatory pathways using the L. (L.) infantum promastigote infected- human monocytic THP-1 cell model and plasma from patients with visceral leishmaniasis. We identified differentially expressed miRNAs in infected THP-1 cells compared with non-infected cells using qPCR arrays. These miRNAs were submitted to in silico analysis, revealing targets within functional pathways associated with TGF-β, chemokines, glucose metabolism, inflammation, apoptosis, and cell signaling. In parallel, we identified differentially expressed miRNAs in active visceral leishmaniasis patient plasma compared with endemic healthy controls. In silico analysis of these data indicated different predicted targets within the TGF-β, TLR4, IGF-I, chemokine, and HIF1α pathways. Only a small number of miRNAs were commonly identified in these two datasets, notably with miR-548d-3p being up-regulated in both conditions. To evaluate the potential biological role of miR-548d-3p, we transiently transfected a miR-548d-3p inhibitor into L. (L.) infantum infected-THP-1 cells, finding that inhibition of miR-548d-3p enhanced parasite growth, likely mediated through reduced levels of MCP-1/CCL2 and nitric oxide production. Further work will be required to determine how miR-548d-3p plays a role in vivo and whether it serves as a potential biomarker of progressive leishmaniasis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

miR-548d-3p Is Up-Regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages

Ramos-Sanchez

Reis

Souza

et al. 2022

Front. Cell. Infect. Microbiol.

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“…miRNAs are regulatory components that can modulate gene expression at the post-transcriptional level and inhibit mRNA translation into proteins [ 19 ]. In addition to numerous studies on miRNA regulations in cancers [ 46 ], many miRNAs are differentially expressed in protozoal diseases, such as cryptosporidiosis [ 47 ], trypanosomosis [ 48 ], leishmaniasis [ 49 ] and toxoplasmosis [ 41 , 43 , 50 ]. Previous studies mainly focused on miRNA changes in cyst-induced toxoplasmosis.…”

Section: Discussionmentioning

confidence: 99%

A combined miRNA–piRNA signature in the serum and urine of rabbits infected with Toxoplasma gondii oocysts

et al. 2022

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Background Increasing evidence has shown that non-coding RNA (ncRNA) molecules play fundamental roles in cells, and many are stable in body fluids as circulating RNAs. Study on these ncRNAs will provide insights into toxoplasmosis pathophysiology and/or help reveal diagnostic biomarkers. Methods We performed a high-throughput RNA-Seq study to comprehensively profile the microRNAs (miRNAs) and PIWI-interacting RNAs (piRNAs) in rabbit serum and urine after infection with Toxoplasma gondii oocysts during the whole infection process. Results Total RNA extracted from serum and urine samples of acutely infected [8 days post-infection (DPI)], chronically infected (70 DPI) and uninfected rabbits were subjected to genome-wide small RNA sequencing. We identified 2089 miRNAs and 2224 novel piRNAs from the rabbit sera associated with T. gondii infection. Meanwhile, a total of 518 miRNAs and 4182 novel piRNAs were identified in the rabbit urine associated with T. gondii infection. Of these identified small ncRNAs, 1178 and 1317 serum miRNAs and 311 and 294 urine miRNAs were identified as differentially expressed (DE) miRNAs in the acute and chronic stages of infections, respectively. A total of 1748 and 1814 serum piRNAs and 597 and 708 urine piRNAs were found in the acute and chronic infection stages, respectively. Of these dysregulated ncRNAs, a total of 88 common DE miRNAs and 120 DE novel piRNAs were found in both serum and urine samples of infected rabbits. Conclusions These findings provide valuable data for revealing the physiology of herbivore toxoplasmosis caused by oocyst infection. Circulating ncRNAs identified in this study are potential novel diagnostic biomarkers for the detection/diagnosis of toxoplasmosis in herbivorous animals. Graphical Abstract

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“…Here, we performed a dual RNAseq analysis to simultaneously profile changes in mRNA and miRNA abundances in primary, bone marrow-derived macrophages infected with lesion-isolated L. amazonensis amastigotes (Lemaire et al 2013, Martinez-Hernandez et al 2021, Rashidi et al 2021, Fernandes et al 2022. Computational analysis of these data sets allowed us to map putative miRNA-mRNA regulatory networks that are predicted to control the observed inhibition of the pro-inflammatory TLR / NF-κB signalling pathway and increased cholesterol biosynthesis, both of which are prerequisites for intracellular parasite survival , Gutierrez Sanchez et al 2023.…”

Section: Introductionmentioning

confidence: 99%

MAPPING CHANGES OF MIRNA-MRNA NETWORKS INLEISHMANIA-INFECTEDMACROPHAGES PREDICTS REGULATORY MIRNA-TF LOOPS AS NOVEL TARGETS OF PARASITE IMMUNE SUBVERSION

Gharsallah,

Lecoeur,

Varet

et al. 2024

Preprint

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MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level and play a crucial role in numerous disease processes, including infections. Although intracellular microbial pathogens are known to modulate host cell gene expression to establish permissive conditions for infection, the specific role of host-encoded miRNAs underlying such subversion remains poorly understood. In this study, we employed the protozoan parasite Leishmania amazonensis as a model system to investigate how infection of macrophages modifies the host cell miRNA profile to evade antimicrobial functions and to establish permissive conditions for intracellular proliferation. Dual RNA-seq analyses using matched mRNA and miRNA-enriched samples from uninfected and L. amazonensis-infected bone marrow-derived macrophages (BMDMs) revealed 102 differentially expressed miRNAs (padj<0.05), with 18 miRNAs showing reduced and 84 miRNAs showing increased abundance in infected BMDMs. Mapping putative networks of miRNA-mRNA interactions based on the observed expression changes, combined with Gene Ontology enrichment analyses, allowed us to identify potential miRNA target genes involved in key biological processes and metabolic pathways that permit parasite intracellular survival and proliferation. Our analyses predict the existence of a large miRNA-mRNA network affecting the expression level of numerous transcription factors that indicates inhibition of the NF-κB-dependent inflammatory response or the promotion of cholesterol biosynthesis during infection. In particular, the over 10e3-fold increase in the abundance of mmu-miR-686 in infected BMDMs was correlated with a reduced abundance of putative target transcripts implicated in miRNA biogenesis itself, in RNA binding, and in regulation of apoptosis, such as Caspase 12, the mRNA decay activator protein Zfp36l1 or Leukemia Inhibitory Factor Receptor Alpha. Likewise, the over 200-fold increase in abundance of mmu-miR-6546-3p was associated with a reduced abundance of putative target mRNAs implicated in cytokine-mediated signaling, positive regulation of apoptotic process and regulation of gene expression, affecting, for example, the MADS box transcription enhancer factor 2, the transformation related protein 53 inducible nuclear protein 1, or the G protein-coupled receptor 35. Interestingly, both miRNAs are predicted to simultaneously target 32 mRNAs that showed reduced abundance in infected BMDMs, including Maturin Neural Progenitor Differentiation Regulator (Mturn), a regulator of NF-κB transcription factor activity. In conclusion, our approach provides novel insight into molecular mechanisms that may govern macrophage subversion and intracellular Leishmania survival. Our results shed new light on the complex relationship among miRNAs, macrophage gene expression and Leishmania infection, proposing regulatory feed-forward loops (FFLs) and feedback loops (FBLs) between miRNAs and TFs as a novel target of Leishmania immune subversion. These findings open exciting new avenues for the development of intervention strategies aimed at disrupting such crucial interactions, for example using an anti-miR (antagomir) approach against mmu-miR-686 and mmu-miR-6546-3p.

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Highlighting the interplay of microRNAs from Leishmania parasites and infected-host cells

Abstract: Abstract

Cited by 12 publications

References 150 publications

miR-548d-3p Is Up-Regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages

miR-548d-3p Is Up-Regulated in Human Visceral Leishmaniasis and Suppresses Parasite Growth in Macrophages

A combined miRNA–piRNA signature in the serum and urine of rabbits infected with Toxoplasma gondii oocysts

MAPPING CHANGES OF MIRNA-MRNA NETWORKS INLEISHMANIA-INFECTEDMACROPHAGES PREDICTS REGULATORY MIRNA-TF LOOPS AS NOVEL TARGETS OF PARASITE IMMUNE SUBVERSION

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