Role of long noncoding RNA HIF1A-AS3 in immunometabolism of murine macrophage infection with Leishmania infantum

• Grant number: 24/06233-1
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: April 10, 2025
• End date: April 09, 2026
• Field of knowledge: Biological Sciences - Parasitology
• Principal Investigator: Sandra Marcia Muxel
• Grantee: Jonathan Miguel Zanatta
• Supervisor: Ricardo Jorge Leal Silvestre
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Universidade do Minho (UMinho), Portugal
• Associated to the scholarship: 22/08700-0 - Study of the glycolytic function of the developmental factor HIF-1a and long noncoding RNA HIF1A-AS3 in the metabolism of macrophages infected with L. infantum, BP.DR

Abstract

The relationship of long noncoding RNAs (lncRNAs) in the immunometabolic connections during Leishmania infection remains poorly tested. Here, we propose an integrative approach to study the function of lncRNA HIF1A-AS3 encoded in HIF1A antisense strand in the Leishmania-induced shifts in metabolic networks in murine macrophages, deciphering the molecular mechanisms of this phenomenon and evaluating the anti-leishmanial immune response. Using L. infantum infection ofWT and HIF1a knockout mice as a model, we will test the novel postulate that manipulating lncRNA regulate metabolic programs to redirect the course of pathogenesis or recovery decisively. We hypothesized that infection with L. infantumchanges the gene expression of HIF-1± and the lncRNA encoded in the antisense strand of HIF1 sequence (HIF1A-AS3) in macrophages and target-genes. The interaction between HIF1A-AS3 and the HIF-1± and its target genes would turn macrophageactivation and immunometabolism, increasing susceptibility to infection. The interaction between HIF-1± and HIF1A-AS3 sets up an activation complex with other factors that lead to increased transcriptional levels of hexokinase II and lactate dehydrogenase genes and glycolysis, as shown in tumor cells. The lncRNAs expressioncan be altered in Leishmania-infected macrophages to mediate the activation of the pro-inflammatory response or subversion of the host response. We and others have previously begun to identify perturbed metabolic niches and the involved actors on Leishmania-infected macrophages and DCs that are particularly relevant to the immune function. Perturbed metabolic fluxes on Leishmania-infected macrophages are particularly relevant since it can crucially affect the activation, differentiation, and functions of this immune cell type and can deterministically direct the outcome of an infection.