Abstract
American Tegumentary Leishmaniasis is a chronic infection caused by Leishmania protozoan. It is not known whether genetic variances in NOD-like receptor (NLR) family members influence the immune response towards Leishmania parasites and modulate intracellular killing. Using functional genomics, we investigated whether genetic variants in NOD1 or NOD2 influence the production of cytokines by human PBMCs exposed to Leishmania. In addition, we examined whether recognition of Leishmania by NOD2 contributes to intracellular killing. Polymorphisms in the NOD2 gene decreased monocyte- and lymphocyte-derived cytokine production after stimulation with L. amazonensis or L. braziliensis compared to individuals with a functional NOD2 receptor. The phagolysosome formation is important for Leishmania-induced cytokine production and upregulation of NOD2 mRNA expression. NOD2 is crucial to control intracellular infection caused by Leishmania spp. NOD2 receptor is important for Leishmania recognition, the control of intracellular killing, and the induction of innate and adaptive immune responses.
Highlights
American Tegumentary Leishmaniasis is a chronic infection caused by Leishmania protozoan
We explored whether single-nucleotide polymorphism (SNP) in NOD-like receptor (NLR) family members NOD1 and NOD2 influence the production of cytokines after stimulation with Leishmania parasites
The results demonstrated that individuals heterozygous for NOD2 Leu1007insC polymorphism displayed significantly lower production of TNFα, IL-1β, IL-6, IL-8 and IFNγ for either L. amazonensis or L. braziliensis stimulation (Fig. 1A,B)
Summary
American Tegumentary Leishmaniasis is a chronic infection caused by Leishmania protozoan. In the most severe cases of Leishmaniasis, L. amazonensis can cause diffuse cutaneous lesions (DCL) and L. braziliensis can cause mucocutaneous lesions (ML)[2] Innate immune cells such as macrophages, neutrophils, and natural killer cells recognize microorganisms through interaction between microbial ligands (MAMPs) with their pattern recognition receptors (PRRs). Following NLRP3 inflammasome activation, IL-1β can be produced and contributes to the control of murine Leishmania infection[13] Besides inflammation, these proinflammatory cytokines are important for controlling the Leishmania infection by inducing microbicidal molecules, such as reactive oxygen and nitrogen intermediates (ROI, RNI), which are crucial for the parasite killing[10,19,20,21,22]
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