Differential Expression of MicroRNAs in Leprosy Skin Lesions

Abstract

Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is a major public health problem in poor and developing countries of the Americas, Africa, and Asia. MicroRNAs (miRNAs), which are small non-coding RNAs (18–24 nucleotides), play an important role in regulating cell and tissue homeostasis through translational downregulation of messenger RNAs (mRNAs). Deregulation of miRNA expression is important for the pathogenesis of various neoplastic and non-neoplastic diseases and has been the focus of many publications; however, studies on the expression of miRNAs in leprosy are rare. Herein, an extensive evaluation of differentially expressed miRNAs was performed on leprosy skin lesions using microarrays. Leprosy patients, classified according to Ridley and Jopling’s classification or reactional states (R1 and R2), and healthy controls (HCs) were included. Punch biopsies were collected from the borders of leprosy lesions (10 tuberculoid, 10 borderline tuberculoid, 10 borderline borderline, 10 borderline lepromatous, 4 lepromatous, 14 R1, and 9 R2) and from 9 HCs. miRNA expression profiles were obtained using the Agilent Microarray platform with miRBase, which consists of 1,368 Homo sapiens (hsa)-miRNA candidates. TaqMan quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) was used to validate differentially expressed miRNAs. Sixty-four differentially expressed miRNAs, including 50 upregulated and 14 downregulated (fold change ≥2.0, p-value ≤ 0.05) were identified after comparing samples from patients to those of controls. Twenty differentially expressed miRNAs were identified exclusively in the reactional samples (14 type 1 and 6 type 2). Eight miRNAs were validated by RT-PCR, including seven upregulated (hsa-miR-142-3p, hsa-miR-142-5p, hsa-miR-146b-5p, hsa-miR-342-3p, hsa-miR-361-3p, hsa-miR-3653, and hsa-miR-484) and one downregulated (hsa-miR-1290). These miRNAs were differentially expressed in leprosy and several other diseases, especially those related to the immune response. Moreover, the integration of analysis of validated mi/mRNAs obtained from the same samples allowed target pairs opposite expression pattern of hsa-miRNA-142-3p and AKR1B10, hsa-miRNA-342-3p and FAM180b, and hsa-miRNA-484 and FASN. This study identified several miRNAs that might play an important role in the molecular pathogenesis of the disease. Moreover, these deregulated miRNAs and their respective signaling pathways might be useful as therapeutic markers, therapeutic targets, which could help in the development of drugs to treat leprosy.

The miR-125a-3p is Associated With Leprosy Phenotypes and Correlated With Bacillary Index

“…Interestingly, miR-125a-3p was also more expressed in individuals with ENL, when compared to MB individuals without reactions. Similarly, Cleverson et al, 2017, identi ed a differential expression of miR-125b-2, in the type 2 reactions [13]. However, the mechanism by which miR-125 participates in the initiation and / or maintenance of the type 2 reaction, in leprosy it is not known.…”

Potential of AKR1B10 as a Biomarker and Therapeutic Target in Type 2 Leprosy Reaction

“…Also, several miRNAs were differentially expressed in the spectral and reactional forms of leprosy. Based on our analysis of mi/mRNA expression, we noted that the expression patterns of hsa-miRNA-142-3p and AKR1B10 opposed each other ( 33 ). These results indicate that the expression of AKR1B10 is regulated by microRNA ( 33 ).…”

“…Based on our analysis of mi/mRNA expression, we noted that the expression patterns of hsa-miRNA-142-3p and AKR1B10 opposed each other ( 33 ). These results indicate that the expression of AKR1B10 is regulated by microRNA ( 33 ). The regulation of mRNA expression by miRNAs is complex, and there are also other mechanisms of epigenetic regulation of gene expression, necessitating further studies to determine whether there is an interaction between hsa-miR-142-3p and AKR1B10 in leprosy.…”

Human genetics of mycobacterial disease

“…RNA expression analyses have provided valuable data to better understanding leprosy pathogenesis. Comparisons of mRNA and miRNA expression between leprotic lesions and skin biopsies of healthy controls showed a large number of genes differentially expressed, including DE mRNAs and miRNAs exclusively detected in samples with leprosy reactions (Belone et al 2015 ; Soares et al 2017 ). Moreover, contrasting nerve biopsies of leprosy lesions against non-leprous neuropathy ones highlighted down-regulated cytokines and genes involved in mitochondrial metabolism as mediators of the host- M. leprae interplay (Guerreiro et al 2013 ).…”