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Metabolic reprogramming of Leishmania-infected human THP-1 macrophages mediated by microRNA

Grant number: 21/09111-6
Support Opportunities:Scholarships abroad - Research Internship - Doctorate (Direct)
Effective date (Start): December 01, 2021
Effective date (End): November 30, 2022
Field of knowledge:Biological Sciences - Parasitology - Protozoology of Parasites
Principal Investigator:Lucile Maria Floeter-Winter
Grantee:Juliane Cristina Ribeiro Fernandes
Supervisor: Coral Barbas
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Research place: Universidad CEU San Pablo, Madrid, Spain  
Associated to the scholarship:17/21906-9 - Role of miRNAs in the regulation of polyamines/NO production pathways in THP-1 derived macrophages infected with Leishmania amazonensis, BP.DD

Abstract

Metabolomic is emerging as an important tool to characterize macrophage phenotype, that, combined to genetic approaches, allows deciphering gene expression regulation in its ultimate phenotype, the metabolism. Metabolic rewiring during Leishmania infection was extensively studied in murine macrophages, but the differences to human immunology are increasingly being studied. Leishmania possess different mechanisms to modulate macrophage metabolism and gene expression, favoring its survival and replication within the hostile phagolysosome environment. Small regulatory non-coding RNAs, the microRNAs, are global regulators of gene expression in macrophages modulating target mRNAs. We have previously shown mmu-miR-294 targeting nitric oxide synthase 2 (Nos2) mRNA in murine macrophage model infected with L. amazonensis. Human THP-1 macrophages upregulate hsa-miR-373, homologous to mmu-miR-294, sharing the same 5' seed sequence. Besides, miR-372 and miR-520d also share this seed sequence and are upregulated in response to L. amazonensis infection, therefore potentially targeting similar miRNAs. To understand the effector power of miRNA regulation controlling macrophage function, we constructed a macrophage cell line that expresses a miRNA sponge impairing miR-373 activity on its targets. The comparison of the metabolic fingerprint of this cell line to the non-modified THP-1 macrophages would provide a big picture of the role of miR-372/373/520d in modulating macrophage metabolism during L. amazonensis infection, together with gene expression analysis and miRNA-target validation techniques. (AU)

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