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Role of miRNAs in the TLRs-mediated immune response to Leishmania amazonensis infection

Grant number: 16/19815-2
Support type:Regular Research Grants
Duration: December 01, 2016 - November 30, 2018
Field of knowledge:Biological Sciences - Parasitology
Principal Investigator:Sandra Marcia Muxel
Grantee:Sandra Marcia Muxel
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Juliana Ide Aoki ; Lucile Maria Floeter-Winter

Abstract

Post-transcriptional regulation mediated by microRNAs in infectious processes caused by bacteria, viruses and parasites, as well as tumor cells, is intensively studied in recent years. The Leishmania infection is also able to modulate the expression of miRNAs and regulate genes involved in macrophage response to parasite. The Leishmania-modulation of miRNAs expression of macrophage could inhibits the production of nitric oxide (NO) directing the L-arginine for the production of polyamines by the increased expression of arginase I of the host, resulting in the survival and replication of the parasite . Understand how the signaling mediated by Toll-like receptors (TLR) operates in the miRNAs and mRNAs target regulatory process is not yet elucidated in models of infection with Leishmania amazonensis.The hypothesis is that the host microRNA expression is modified during entry and replication of L. amazonensis in macrophages. Its being mediated by recognition through innate immune receptors, as TLR, for subvert the host immune response. Thus, activation of the TLR signaling pathway could modulates the expression of miRNAs involved in post-transcriptional control of intracellular signaling of the innate immunity receptor pathways, or the modulation miRNAs expression could regulates the activation of the TLRs. Still, modulation of miRNA mediated by TLR, or vice versa, would have a functional role in the maturation of the phagolysosome, in activation of cytokine production, activation of NF-kB signaling pathway or polyamine/NO production pathways (arginase1/NOS2).The central idea of this project is to investigate whether signaling via MyD88, TLR2 or TLR4 during infection of macrophages modulate the composition of the host miRNAs and induce the macrophage to phagocyte and eliminate the parasite. Still, understanding the modulation of miRNA composition due to change in the way of recognizing the parasite and contributes to the activation of macrophages and the immune response generated during leishmaniasis. Thus, this project is mainly aimed to evaluate the microRNAs expression in macrophages derived from MyD88, TLR2 or TLR4 knockout mice infected with L. amazonensis and its implications in the regulation of phagocytosis, production of polyamines and NO pathways and consequent parasite survival. The miRNAs differential expressed, that have relevance to the routes studied, will be used as "candidates" in silencing studies of its impact on gene expression and infectivity. (AU)

Scientific publications (5)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
AOKI, JULIANA IDE; LARANJEIRA-SILVA, MARIA FERNANDA; MUXEL, SANDRA MARCIA; FLOETER-WINTER, LUCILE MARIA. The impact of arginase activity on virulence factors of Leishmania amazonensis. Current Opinion in Microbiology, v. 52, p. 110-115, DEC 2019. Web of Science Citations: 0.
RIBEIRO FERNANDES, JULIANE CRISTINA; AOKI, JULIANA IDE; ACUNA, STEPHANIE MAIA; ZAMPIERI, RICARDO ANDRADE; MARKUS, REGINA P.; FLOETER-WINTER, LUCILE MARIA; MUXEL, SANDRA MARCIA. Melatonin and Leishmania amazonensis Infection Altered miR-294, miR-30e, and miR-302d Impacting on Tnf, Mcp-1, and Nos2 Expression. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 9, MAR 20 2019. Web of Science Citations: 2.
MUXEL, SANDRA MARCIA; ACUNA, STEPHANIE MAIA; AOKI, JULIANA IDE; ZAMPIERI, RICARDO ANDRADE; FLOETER-WINTER, LUCILE MARIA. Toll-Like Receptor and miRNA-let-7e Expression Alter the Inflammatory Response in Leishmania amazonensis-Infected Macrophages. FRONTIERS IN IMMUNOLOGY, v. 9, NOV 29 2018. Web of Science Citations: 3.
MUXEL, SANDRA M.; AOKI, JULIANA I.; FERNANDES, JULIANE C. R.; LARANJEIRA-SILVA, MARIA F.; ZAMPIERI, RICARDO A.; ACUNA, STEPHANIE M.; MULLER, KARL E.; VANDERLINDE, RUBIA H.; FLOETER-WINTER, LUCILE M. Arginine and Polyamines Fate in Leishmania Infection. FRONTIERS IN MICROBIOLOGY, v. 8, JAN 15 2018. Web of Science Citations: 12.
ACUNA, STEPHANIE MAIA; AOKI, JULIANA IDE; LARANJEIRA-SILVA, MARIA FERNANDA; ZAMPIERI, RICARDO ANDRADE; RIBEIRO FERNANDES, JULIANE CRISTINA; MUXEL, SANDRA MARCIA; FLOETER-WINTER, LUCILE MARIA. Arginase expression modulates nitric oxide production in Leishmania (Leishmania) amazonensis. PLoS One, v. 12, n. 11 NOV 14 2017. Web of Science Citations: 10.

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