Integrative study of Long noncoding RNAs and microRNAs in Leishmania infection

Abstract

The modulation of macrophage activation is mediated by long noncoding RNA (lncRNA) and microRNAs (miRNAs), acting in the transcriptional and/or post-transcriptional regulation of genes that can promote the death of Leishmania. lncRNAs regulate chromosomal structure, mRNA transcription, splicing and protein translation. MiRNAs regulate the translation and degradation of the target gene transcript by interacting with the 3'UTR region of the mRNA. We formulated the hypothesis that Leishmania recognition via TLR and parasite metabolism interfere with the expression of long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) and these regulate the immune response and macrophage metabolism during infection. To test this hypothesis, we aimed to evaluate the function of lncRNA and miRNAs in regulating the immune response and metabolism in macrophages infected with Leishmania and the consequences for infection in vivo. We will use transcriptomic approaches and interference in the expression of lncRNA and miRNAs and the use of drugs as an experimental strategy. lncRNAs and miRNAs in macrophages in the inflammatory context or Leishmania infection regulate the production of TNF, IL-1² and IL-6 cytokines, glycolysis and nitric oxide production, and consequently microbicidal activity. lncRNAs and miRNAs are encoded in the genome in intronic or antisense regions of genes, such as lncRNA-HIF1A-AS3 and HIF-1± (glycolysis gene regulator), miR-372/373 and NALP12 (negative inflammasome regulator) and miR -302 and LARP7 (transcription regulator), forming intricate gene regulatory networks. Furthermore, the use of drugs that compete with the PEX5/PEX14 interaction and targeting enzymes to the parasite's glycosome will help us understand how the parasite's metabolism alters the expression of microRNAs and the microbicidal capacity in macrophages. In order to identify targets related to the immune response and metabolism to reduce susceptibility to Leishmania infection, we focused on understanding the networks of transcriptional and post-transcriptional regulations mediated by lncRNAs and miRNAs to seek therapeutic strategies. (AU)