Integration of signaling mediated by transcription factors, long-noncoding RNAs and microRNAs during immune response agaisnt Leishmania amazonensis infection

Abstract

The control of gene expression is a complex network that could be mediated by three regulators: 1) transcription factors (TFs), via binding to regulatory DNA regions such as promoters or enhancers in the target gene that regulated mRNA transcription; 2) long noncoding RNA (lncRNA), via interaction with DNA, RNA or protein, regulating the chromosomal structure, transcription of mRNAs and microRNAs (miRNAs), their splicing and even acting in the translation of proteins; and 3) miRNAs, via complementation with the 3'UTR of the target mRNA, regulating translation or establishing the degradation of the target gene transcript. Some TFs and miRNAs have benn described in the modulation host response to Leishmania infection. Therefore, the analysis of the expression profile and regulation mediated by TFs (NF-kB, IRF1 and Cux1), lncRNAs and miRNAs from macrophages infected by Leishmania amazonensis, will allow the understanding of how complex is the modulation of host gene expression network in response to parasite. Leishmania infection is strongly influenced by host genetic background. On the other hand, the parasite is able to subvert the host defenses through L-arginine metabolism to produce polyamines, in addition to expression regulation of cytokines and chemokines, resulting in parasite survival and replication. The central objective of this project is to evaluate the expression of TFs, lncRNAs and microRNAs, and metabolites, in human macrophages (derived from the THP-1 line) and BALB/c and C57BL/6 mice macrophages infected by L. amazonensis and to elucidate the role of each regulator in the infection control or in the parasite resistance against the immune response of different hosts. These data will allow to identify potential genetic markers capable to determine the disease prognosis. This project has the potential to produce scientific articles and presentations in national and international conferences, besides serves as an instrument for the intellectual formation and training of students. (AU)