miRNome Expression Analysis Reveals New Players on Leprosy Immune Physiopathology

Abstract

Leprosy remains as a public health problem and its physiopathology is still not fully understood. MicroRNAs (miRNA) are small RNA non-coding that can interfere with mRNA to regulate gene expression. A few studies using DNA chip microarrays have explored the expression of miRNA in leprosy patients using a predetermined set of genes as targets, providing interesting findings regarding the regulation of immune genes. However, using a predetermined set of genes restricted the possibility of finding new miRNAs that might be involved in different mechanisms of disease. Thus, we examined the miRNome of tuberculoid (TT) and lepromatous (LL) patients using both blood and lesional biopsies from classical leprosy patients (LP) who visited the Dr. Marcello Candia Reference Unit in Sanitary Dermatology in the State of Pará and compared them with healthy subjects. Using a set of tools to correlate significantly differentially expressed miRNAs with their gene targets, we identified possible interactions and networks of miRNAs that might be involved in leprosy immunophysiopathology. Using this approach, we showed that the leprosy miRNA profile in blood is distinct from that in lesional skin as well as that four main groups of genes are the targets of leprosy miRNA: (1) recognition and phagocytosis, with activation of immune effector cells, where the immunosuppressant profile of LL and immunoresponsive profile of TT are clearly affected by miRNA expression; (2) apoptosis, with supportive data for an antiapoptotic leprosy profile based on BCL2, MCL1, and CASP8 expression; (3) Schwann cells (SCs), demyelination and epithelial–mesenchymal transition (EMT), supporting a role for different developmental or differentiation gene families, such as Sox, Zeb, and Hox; and (4) loss of sensation and neuropathic pain, revealing that RHOA, ROCK1, SIGMAR1, and aquaporin-1 (AQP1) may be involved in the loss of sensation or leprosy pain, indicating possible new therapeutic targets. Additionally, AQP1 may also be involved in skin dryness and loss of elasticity, which are well known signs of leprosy but with unrecognized physiopathology. In sum, miRNA expression reveals new aspects of leprosy immunophysiopathology, especially on the regulation of the immune system, apoptosis, SC demyelination, EMT, and neuropathic pain.

Advances in the Immunology and Genetics of Leprosy

“…This study not only showed how macrophage divergence occurred at the site of infection but also provided new clues for intervening in intracellular infections. Moreover, a recent study focusing on miRNAome expression in leprosy physiopathology found that miR-34a-5p which controlled JAG1 expression was upregulated in lepromatous leprosy (L-lep) lesions (17). Thus, downregulation of JAG1 by miR-34a-5p allows the differentiation of M2 macrophage in L-lep, which is consistent with the discovery of a JAG1-dependent M1 macrophage differentiation (16).…”

“…Further analysis indicated that hsa-mir-21 could inhibit the expression of two vitamin D-dependent antimicrobial peptides by downregulating the Toll-like receptor 2/1 (TLR 2/1) pathway and upregulating IL- 10 (18), which clearly demonstrated the interaction between leprosy pathogens and macrophage antimicrobial activity. In addition, other miRNAs targeting TLR4 and IL15R, which also regulated the vitamin D-dependent antimicrobial pathway, were also observed to be upregulated in L-lep, indicating the inhibition of vitamin Ddependent antimicrobial pathway (17). These studies repeatedly demonstrated the role of vitamin D-dependent antimicrobial pathway in the control of M. leprae infection.…”

The cell fate regulator NUPR1 is induced by Mycobacterium leprae via type I interferon in human leprosy

“…Furthermore, some alleles of PARK2 gene, a ubiquitin ligase involved in ubiquitin-mediated autophagy of mycobacteria, are associated with leprosy susceptibility [59, 60]. Apoptosis has also been detected more frequently in the T-lep skin lesions when compared to L-lep specimens [38, 39, 61], which can be associated with higher expression of the anti-apoptotic molecule BCL-2 in lepromatous skin lesions [39, 61].…”

Neurological Complications of Leprosy

“…Importantly, the miRNA profile of leprosy in blood and skin lesions were found to be distinct, suggesting a different mechanism of disease affecting the two organs. 31 In terms of neuropathy in M. leprae, it is thought to involve localization of the bacterium to the nerve, infection of Schwann cells, and host immune response causing edema and inflammation that contribute to injury. Recent research has focused on the role of nerve growth factor for its proapoptotic effects upon binding to Schwann cells and oligodendrocytes.…”