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.
Highlights
American tegumentar leishmaniasis (ATL) is a complex, multifactorial disease that results from environmental factors such as parasite polymorphisms, phlebotomine sand fly components, as well as the host’s immune and genetic background [1]
The study was conducted in the rural area of Corte de Pedra, Bahia, Brazil, where American Tegumentary Leishmaniasis (ATL) caused by L. braziliensis is endemic
While molecular biologists will focus on identifying and characterizing circumstances where miRNAs are acting as gene regulatory switches, bioinformaticians will have to deal with the prospect that a substantial fraction of all animal mRNAs could have their level of expression influenced by miRNA regulation [35]
Summary
American tegumentar leishmaniasis (ATL) is a complex, multifactorial disease that results from environmental factors such as parasite polymorphisms, phlebotomine sand fly components, as well as the host’s immune and genetic background [1]. DL compared to CL has been associated with lower IFN-γ and TNF production, higher IL-5 production, and anti-Leishmania antibodies, with variable T cell response among affected individuals [11] As a whole, this complex disease depends on both the extent of parasite elimination and the relative induction of potentially immunopathologic responses [7]. 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. In this study we used a previously published transcriptional analysis comparing CL lesion samples and normal skin of patients infected L. braziliensis (GEO accession number GSE55664), which showed that genes associated with inflammatory cell recruitment (CXCL9, CXCL10, and CCL8) and cytotoxicity (GZMA, GZMB, and GLYN) were highly expressed in L. braziliensis lesions. Based on this previous study, we aimed to identify the miRNAs that could act as regulators of differentially genes found in CL lesions and be potential markers of immune response and tissue damage, as well as modifiers of clinical parameters such as disease severity, response to treatment and healing time
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