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Role of miRNAs in the regulation of polyamines/NO production pathways in THP-1 derived macrophages infected with Leishmania amazonensis

Grant number: 17/21906-9
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): March 01, 2018
Effective date (End): February 28, 2022
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal researcher:Lucile Maria Floeter-Winter
Grantee:Juliane Cristina Ribeiro Fernandes
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Leishmania is an obligate intracellular parasite in the mammalian host, infecting phagocytic cells of the immune system. Inside the macrophage, the amastigote form is capable of subverting the hostile environment of the phagolysosome modulating host gene expression for its survival. L-arginine is a common substrate for both Nitric Oxide (NO) or polyamines production by macrophage enzymes nitric oxide synthase 2 (NOS2) or arginase 1 (ARG1), respectively. The parasite presence favors the production of polyamines, essential molecules for its survival and proliferation, in detriment of NO production, the main effector molecule that leads parasites to death. Besides, the parasite is able to conduct de novo polyamine synthesis. Studies using Leishmania amazonensis arginase knockout model had demonstrated that arginase is essential for parasite survival and that the enzyme activity is involved in the modulation of host response.The activity of miRNAs on target mRNAs has been described as an important mechanism in the control of immune response against the infection. Since Leishmania modifies the expression of host miRNAs, this project aims to elucidate the role of the post-transcriptional regulation of gene expression mediated by miRNAs in regulating the uptake and the metabolism of L-arginine to determine the molecular mechanisms involved in the establishment of L. amazonesis infection in human THP-1 macrophages. (AU)