Abstract

Toll-like receptors (TLRs) have significant involvement in Leishmania infection, although little is known about the relationship between these receptors, cytokines and nitric oxide (NO) in patients with visceral leishmaniasis (VL) before or after treatment with anti-leishmanial drugs. The goal of this study was to evaluate the expression of TLR2 and TLR4 in CD3+ and CD14+ cells and the production of TNF-α, IFN-γ, IL-17, IL-10, TGF-β and NO in peripheral blood mononuclear cells (PBMCs) from VL patients pre- and post-treatment with anti-leishmanial drugs. In addition, we investigated whether these receptors were involved in the production of these cytokines and NO. In the active VL patients, increased TLR2 and TLR4 expression in lymphocytes and monocytes, increased production of TNF-α, IL-10 and TGF-β and decreased production of IFN-γ, IL-17 and NO were observed. After treatment, TLR2 and TLR4 were still expressed in lymphocytes and monocytes, the TNF-α and IL-10 levels were lower, the production of IFN-γ, IL-17 and NO was higher, and the TGF-β level remained high. Before treatment, the production of TNF-α and NO was associated with TLR2 and TLR4 expression, while IL-10 production was only associated with TLR2 expression. After treatment, both receptors were associated with the production of TNF-α, IFN-γ, IL-10 and NO, while the production of IL-17 was associated only with TLR4 expression. The results presented in this study suggest that both TLR2 and TLR4 participate in the modulation of cytokine and NO production in VL patients, contributing to the pathogenesis of VL prior to treatment and the protective immune response after treatment.

Highlights

  • Visceral leishmaniasis (VL), known as Kala Azar, is caused by infection with obligate intracellular protozoa belonging to the Leishmania donovani complex [1,2]

  • The expression and coexpression of TLR2 and TLR4 on the surface of lymphocytes and monocytes was assessed by measuring the percentage of CD3+ and CD14+ cells positive for TLR2

  • Regarding the mean fluorescence intensity (MFI) (Fig. 1B and C), there were no significant differences in the expression of TLR2 or TLR4 in CD3+ cells from pre-treatment patients compared with post-treatment patients and control individuals

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Summary

Introduction

Visceral leishmaniasis (VL), known as Kala Azar, is caused by infection with obligate intracellular protozoa belonging to the Leishmania donovani complex [1,2]. This disease is fatal if left untreated, and its symptoms include hepatosplenomegaly, fever, anemia, weight loss, hyperglobulinemia and pancytopenia [3]. Regarding VL treatment, pentavalent antimonials represent the first choice of treatment in Brazil [6,7]. Amphotericin B can be used in cases of toxicity or in patients with poor responses to antimonial therapy, and this drug is the first choice for treating pregnant patients and terminal cases of VL disease [8,9]. According to the guidelines of The Brazilian Ministry of Health, patients older than 50 years, patients with Chagas disease or patients diagnosed with renal, hepatic or cardiac complications should be treated with colloidal or lipid formulations of amphotericin B [7]

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