Functional circuit analysis of miR-372/373 with HIF1A in Leishmania infantum infection

• Grant number: 25/10345-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2025
• End date: June 30, 2026
• 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
• Associated research grant: 24/08802-3 - Integrative study of Long noncoding RNAs and microRNAs in Leishmania infection, AP.R

Abstract

HIF-1¿ (hypoxia-inducible factor-1¿) is a transcription factor involved in the regulation of genes associated with glycolytic metabolism and lactate production pathways. In macrophages, HIF-1¿ is activated in response to PAMPs, such as lipopolysaccharide (LPS). This activation leads to reprogramming of carbohydrate and lipid metabolism and promotes inflammation. MicroRNAs are small non-coding RNAs that regulate gene expression by pairing their seed region (6-9 nt) with complementary sequences in the 3' UTR of target mRNAs, promoting mRNA degradation or translation inhibition. In our previous data, we observed an increase in miR-372 and miR-373 in THP-1 macrophages infected with L. amazonensis, and functional inhibition of these microRNAs reduced infection. In this project, our goal is to understand the role of miR-372 and miR-373 in regulating HIF1A and its target gene network, as well as their impact on the response of macrophages infected with Leishmania infantum. Our results indicate that infection with L. infantum in THP-1-derived macrophages induces the expression of miR-372 and miR-373 and decreases the expression of the transcription factor HIF1A. There was also an increase in the expression of HIF1A target genes such as PDK1, and predicted targets of miR-372/373, LDHA and GLUT1, which are also induced by HIF1A. The experiment analyzing L. infantum infection under inhibition of miR-372 and miR-373 revealed a reduction in the number of infected macrophages and amastigotes per macrophage, as assessed by flow cytometry. The BEPE project, in partnership with Prof. Coral Barbas (CEMBIO, Universidad San Pablo, Madrid, Spain), involving analysis of glucose metabolism during L. infantum infection in relation to the action of miR-372/373, also demonstrated that miR-372/373 participate in the regulation of HIF1A in a metabolomic analysis of glycolytic pathway compounds. Therefore, it is important to understand the correlation between the expression of miR-372/373 and HIF-1¿ in macrophages infected with Leishmania, and how modulation of these molecules impacts the activation of the pro-inflammatory response and host response subversion during parasitic infection. (AU)