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

Abstract

L. (viannia) braziliensis infection causes American Tegumentary Leishmaniasis (ATL), with prolonged time to healing lesions. The potent inflammatory response developed by the host is important to control the parasite burden and infection however an unbalanced immunity may cooperate to the tissue damage observed. The range of mechanisms underlying the pathological responses associated with ATL still needs to be better understood. That includes epigenetic regulation by non-coding MicroRNAs (miRNAs), non-coding sequences around 22 nucleotides that act as post-transcriptional regulators of RNAs encoding proteins. The miRNAs have been associated with diverse parasitic diseases, including leishmaniasis. Here we evaluated miRNAs that targeted genes expressed in cutaneous leishmaniasis lesions (CL) by comparing its expression in both CL and normal skin obtained from the same individual. In addition, we evaluated if the miRNAs expression would be correlated with clinical parameters such as therapeutic failure, healing time as well as lesion size. The miR-361-3p and miR-140-3p were significantly more expressed in CL lesions compared to normal skin samples (p = 0.0001 and p < 0.0001, respectively). In addition, the miR-361-3p was correlated with both, therapeutic failure and healing time of disease (r = 0.6, p = 0.003 and r = 0.5, p = 0.007, respectively). In addition, complementary analysis shown that miR-361-3p is able to identify with good sensitivity (81.2%) and specificity (100%) patients who tend to fail initial treatment with pentavalent antimonial (Sbv). Finally, the survival analysis considering “cure” as the endpoint showed that the higher the expression of miR-361-3p, the longer the healing time of CL. Overall, our data suggest the potential of miR-361-3p as a prognostic biomarker in CL caused by L. braziliensis.

MicroRNAs: Biological Regulators in Pathogen–Host Interactions

“…Interestingly, miR-21 is upregulated in peripheral blood mononuclear cells (PBMCs) infected with L. donovani, and miR-blocking increases the expression of IL-12 mRNA in murine-DCs infected with L. donovani, leading to a proliferation of CD4 + T cells [84]. Further, miRNA-361-3p, a regulator of TNF, was observed to be negatively correlated with localized cutaneous leishmaniasis (LCL) skin lesions caused by L. braziliensis, which is resistant to pentavalent antimonial and healing of parasites [85], while the expression of miR-193b and miR-671 was observed to be correlated with that of their respective target genes, CD40 and TNFR, in lesions of L. braziliensis-infected patients.…”

MiR-361-3p inhibits β-amyloid accumulation and attenuates cognitive deficits through targeting BACE1 in Alzheimer's disease

“…Besides that, miR-9, miR-124a, miR-125b, were dysregulated and contributed to neuronal dysfunction in AD (Lukiw, 2007). It is a prognostic biomarker in cutaneous leishmaniasis caused by L. braziliensis (Lago et al, 2018). Its expression was associated with better survival outcomes in cervical cancer (Hu et al, 2018).…”

“…Inhibition of miR-206 increased the level of brain-derived neurotrophic factor (BDNF) improved memory of AD mice (Lee et al, 2012). Particularly, miR-361-3p, an important miRNA in the regulation of non-small cell lung cancer (Chen et al, 2016), pancreatic ductal adenocarcinoma (Hu et al, 2018), cervical cancer (Hu et al, 2018) and cutaneous leishmaniasis lesions (Lago et al, 2018), have been reported to be downregulated in AD (Wang et al, 2011). However, the pathological effect of miR-361-3p in AD and the possible molecular mechanisms are still poorly investigated.…”

Role of a novel circulatory RNA‐based biomarker panel expression in ovarian cancer

“…Wang et al proposed that many miRNAs, including miR‐361‐3p, can modulate TLRs signaling especially TLR2 and TLR4 in human mesenchymal stem cells . Noteworthy, miR‐361‐3p mediates recruitment of +T cells in response to various infections such as Leishmania braziliensis and cancers, thus to produce inflammatory cytokine TNF family increasing cytotoxicity of tumor cells …”