<i>Leishmania</i> regulates host macrophage miRNAs expression by engaging transcription factor c-Myc

Nandan, Devki; Rath, Carolina Torturella; Reiner, Neil E.

doi:10.1002/jlb.4ru0920-614r

Cited by 6 publications

(6 citation statements)

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“…Thus, MYC exerts transcriptional and non-transcriptional control over DNA replication. The regulatory sphere of MYC extends beyond transcriptional regulation as it also controls the expression of miRNAs [ 25 ]. MYC activates miR-17-92, a well-characterized miRNA involved in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Collaborating single-cell and bulk RNA sequencing for comprehensive characterization of the intratumor heterogeneity and prognostic model development for bladder cancer

Wang,

Zuo,

et al. 2023

Aging

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Introduction: Gaining a deeper insight into the single-cell RNA sequencing (scRNA-seq) results of bladder cancer (BLCA) provides a transcriptomic profiling of individual cancer cells, which may disclose the molecular mechanisms involved in BLCA carcinogenesis. Methods: scRNA data were obtained from GSE169379 dataset. We used the InferCNV software to determine the copy number variant (CNV) with normal epithelial cells serving as the reference, and performed the pseudo-timing analysis on subsets of epithelial cell using Monocle3 software. Transcription factor analysis was conducted using the Dorothea software. Intercellular communication analysis was performed using the Liana software. Cox analysis and LASSO regression were applied to establish a prognostic model. Results: We investigated the heterogeneity of tumors in four distinct cell types of BLCA cancer, namely immune cells, endothelial cells, epithelial cells, and fibroblasts. We evaluated the transcription factor activity of different immune cells in BLCA and identified significant enrichment of TCF7 and TBX21 in CD8+ T cells. Additionally, we identified two distinct subtypes of cancer-associated fibroblasts (CAFs), namely iCAFs and myoCAFs, which exhibited distinct communication patterns. Using sub-cluster and cell trajectory analyses, we identified different states of normal-to-malignant cell transformation in epithelial cells. TF analysis further revealed high activation of MYC and SOX2 in tumor cells. Finally, we identified five model genes (SLCO3A1, ANXA1, TENM3, EHBP1, LSAMP) for the development of a prognostic model, which demonstrated high effectiveness in stratifying patients across seven different cohorts. Conclusions: We have developed a prognostic model that has demonstrated significant efficacy in stratifying patients with BLCA.

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Section: Discussionmentioning

confidence: 99%

Collaborating single-cell and bulk RNA sequencing for comprehensive characterization of the intratumor heterogeneity and prognostic model development for bladder cancer

Wang,

Zuo,

et al. 2023

Aging

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“…Although up-regulation of many miRNAs in L . donovani -infected macrophages was reported, miRNA down-regulation was attributed to the enhanced stability of c-Myc, a transcription factor that binds to the miRNA-related promoters and influences deacetylation to repress miRNA biosynthesis but promote parasite survival; c-Myc blockade reduced amastigote survival [ 27 , 28 ]. Wild-type and arginase-deficient L .…”

Section: Leishmania Regulates Micrornas Expression In Macrop...mentioning

confidence: 99%

“…L. donovani isolates from visceral leishmaniasis (VL)AU : Pleaseprovidethefulls and In humans, most miRNAs were overexpressed in L. donovani-infected, but not as much in L. major-infected, macrophages and DCs [21]. Although up-regulation of many miRNAs in L. donovani-infected macrophages was reported, miRNA down-regulation was attributed to the enhanced stability of c-Myc, a transcription factor that binds to the miRNA-related promoters and influences deacetylation to repress miRNA biosynthesis but promote parasite survival; c-Myc blockade reduced amastigote survival [27,28]. Wild-type and arginase-deficient L. amazonensis differentially influence miRNA expression in mouse macrophages suggesting a role for Leishmania-expressed arginase in modulating the macrophage miRNA expression [19].…”

Section: Leishmania Regulates Micrornas Expression In Macrophagesmentioning

confidence: 99%

Bidirectional cytokine-microRNA control: A novel immunoregulatory framework in leishmaniasis

et al. 2022

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As effector innate immune cells and as a host to the protozoan parasite Leishmania, macrophages play a dual role in antileishmanial immunoregulation. The 2 key players in this immunoregulation are the macrophage-expressed microRNAs (miRNAs) and the macrophage-secreted cytokines. miRNAs, as small noncoding RNAs, play vital roles in macrophage functions including cytokines and chemokines production. In the reverse direction, Leishmania-regulated cytokines alter miRNAs expression to regulate the antileishmanial functions of macrophages. The miRNA patterns vary with the time and stage of infection. The cytokine-regulated macrophage miRNAs not only help parasite elimination or persistence but also regulate cytokine production from macrophages. Based on these observations, we propose a novel immunoregulatory framework as a scientific rationale for antileishmanial therapy.

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“…First, Leishmania infection has been correlated to changes in host miRNA abundance, known to limit the expression of pro-inflammatory genes, thus favoring parasite survival (Lemaire et al 2013, Mukherjee et al 2015, Tiwari et al 2017, Muxel et al 2018, Nandan et al 2021, Ganguly et al 2022. Second, intracellular infection by Leishmania causes important changes in the macrophage DNA methylation pattern, affecting signaling pathways, oxidative phosphorylation, and cell adhesion (Marr et al 2014).…”

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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Leishmania regulates host macrophage miRNAs expression by engaging transcription factor c-Myc

Cited by 6 publications

References 84 publications

Collaborating single-cell and bulk RNA sequencing for comprehensive characterization of the intratumor heterogeneity and prognostic model development for bladder cancer

Collaborating single-cell and bulk RNA sequencing for comprehensive characterization of the intratumor heterogeneity and prognostic model development for bladder cancer

Bidirectional cytokine-microRNA control: A novel immunoregulatory framework in leishmaniasis

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

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