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Analysis of miR-372 and miR-373 in the regulation of HIF1A in macrophages infected with Leishmania infantum

Grant number: 23/15730-6
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): February 01, 2024
Effective date (End): January 31, 2025
Field of knowledge:Biological Sciences - Parasitology
Principal Investigator:Sandra Marcia Muxel
Grantee:Bruno Prado Eleuterio
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

In this project, we aim to understand the function of miR-372 and miR-373 in the regulation of HIF1A and its network of target genes and the impact on the response of macrophages infected with Leishmania infantum. We formulate the hypothesis that infection with L. infantum leads an increase the of miR-372/373 expression and these molecules alter the levels of HIF-1± mRNA/protein and, consequently, a network of target genes involved in glycolysis and cytokine production in macrophages, increasing susceptibility to infection. HIF-1± (hypoxia inducible factor-1±) is a transcription factor related to the expression of genes that participate in glycolytic metabolism and the lactate production pathway. In macrophages, HIF-1± is activated in response to PAMPs such as lipopolysaccharide (LPS). With this, there is a reprogramming of carbohydrate and lipid metabolism and an induction of inflammation. The microRNAs are small non-protein-coding RNAs that regulate gene expression by pairing their seed (6-9 nt) with the complementary 3'UTR sequence of the target mRNA, promoting degradation or inhibition of mRNA translation. In our previous data, we observed increased miR-372 and miR-373 in THP-1 macrophages infected with L. amazonensis and functional inhibition of these miRNA reduced infection. The human miR-372-373 cluster is homologous to the mouse miR-294-295 cluster. miR-294 is increased in infection with L. amazonensis and interferes with NO production. Therefore, it is important to understand the correlation between the expression of miR-372/373 and HIF-1± in Leishmania-infected macrophages and how the modulation of these molecules impacts the activation of the pro-inflammatory response and subversion of the host response to the parasite.

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