Integrated Analysis Reveals That miR-193b, miR-671, and TREM-1 Correlate With a Good Response to Treatment of Human Localized Cutaneous Leishmaniasis Caused by Leishmania braziliensis

Abstract

Localized cutaneous leishmaniasis (LCL) is a chronic disease characterized by ulcerated skin lesion(s) and uncontrolled inflammation. The mechanisms underlying the pathogenesis of LCL are not completely understood, and little is known about posttranscriptional regulation during LCL. MicroRNAs (miRNAs) are non-coding small RNAs that regulate gene expression and can be implicated in the pathogenesis of LCL. We investigated the involvement of miRNAs and their targets genes in human LCL using publicly available transcriptome data sets followed by ex vivo validation. Initial analysis highlighted that miRNA expression is altered during LCL, as patients clustered separately from controls. Joint analysis identified eight high confidence miRNAs that had altered expression (−1.5 ≤ fold change ≥ 1.5; p < 0.05) between cutaneous ulcers and uninfected skin. We found that the expression of miR-193b and miR-671 are greatly associated with their target genes, CD40 and TNFR, indicating the important role of these miRNAs in the expression of genes related to the inflammatory response observed in LCL. In addition, network analysis revealed that miR-193b, miR-671, and TREM1 correlate only in patients who show faster wound healing (up to 59 days) and not in patients who require longer cure times (more than 60 days). Given that these miRNAs are associated with control of inflammation and healing time, our findings reveal that they might influence the pathogenesis and prognosis of LCL.

The miRNA 361-3p, a Regulator of GZMB and TNF Is Associated With Therapeutic Failure and Longer Time Healing of Cutaneous Leishmaniasis Caused by L. (viannia) braziliensis

“…In leishmaniasis, there is now a body of evidence showing that the host's miRNAs repertoire is affected upon Leishmania infection and that might interfere with immunity pathways ( 24 , 25 , 36 , 37 ). Nevertheless, regarding LTA, the only documentation associating miRNAs with L. braziliensis infection was recently published by Nunes et al ( 26 ). The present study shows that miR-361-3p and−140-3p were significantly more expressed in CL lesions as compared to the normal skin.…”

“…In addition, there was a species-specific global downregulation in miRNA expression among host cells following infection with L. major and L. donovani , which showed enrichment of MAP kinase, JAK-STAT, and TGF-β signaling pathways after in silico - predicted targets analysis ( 25 ). Finally, in a recent study, the miR-193b, miR-671, and TREM1 were correlated with faster wound healing in patients infected by L. braziliensis ( 26 ). All together these data support the idea that the host cell undergoes selection and specific miRNA regulation after infection with Leishmania parasites.…”

Leishmania-Host Interactions—An Epigenetic Paradigm

“…miRNA-361-3p and−140-3p have been reported to be more expressed in skin lesions caused by L. braziliensis in localized cutaneous leishmaniasis (LCL) (61). While miR-193b and−671 have been correlated with faster wound healing in L. braziliensis infected patients (31). Autophagy in intramacrophagic L. major has been correlated with miRNA-101c,−129-5p and via inhibiting miRNA-210 (28).…”

“…miRNAs are also known to be involved in activation of monocytes through toll-like receptor (TLR) signaling (31). Following infection with L. major and L. donovani , miRNA expression was down modulated through MAP kinase, JAK-STAT, and TGF-β signaling pathways (31).…”

Human microRNAs in host–parasite interaction: a review

“…On the other hand, it has been stated that miR-361-3p and miR-140-3p were significantly overexpressed in cutaneous leishmaniasis lesions (CL) generated by L. braziliensis infection as compared to normal skin samples targeting genes involved in worsening of tissue damage such as TNF, Granzyme B (GZMB), Filaggrin-2 (FLG2) and Natural Killer cell Granule protein 7 (NKG7) (Lago et al 2018). While downregulation of miR-193b and upregulation of miR-671 are correlated with their respective target genes CD40 and TNF receptors (TNFR) modulating the inflammatory response in lesions caused by this parasite (Nunes et al 2018). In addition, Lemaire and colleagues (2013)…”