Analysis of role of miRNAs and transcription factors on the regulation of gene exp...
| 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)