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Gene expression global analysis of genetically modified macrophages with the allelic variant (L162V): evaluation of the role of the human PPAR± gene in the establishment of Leishmania infantum infection

Abstract

Activated peroxisome proliferation receptors (PPARs) make up a subfamily of nuclear receptors. Three isoforms, encoded by separate genes, were identified so far: PPAR±, PPAR² and PPAR³. These receptors, which act as transcription factors, exhibit different functions and distributions in tissues. To date, it has been known that the genes regulated by PPARs participate mainly in the regulation of key proteins, involved in the intra- and extracellular metabolism of lipids, oxidation of fatty acids and inflammatory processes. PPAR±, in particular, is expressed in a number of metabolically active tissues, including liver, kidney, heart, skeletal muscle, adipose tissue, and macrophages that play an important role in lipid metabolism as well as being part of the immune system. Due to its influence on lipid regulation and the fact that its activity is easily modulated by synthetic drugs, PPAR± is considered a very important target for the effective treatment of dyslipidemias.Lipid disorders have been reported in human patients and even in dogs with active Visceral Leishmaniasis (LV). LV in Brazil is a parasitic disease caused by infection of host macrophages by the protozoan Leishmania infantum and transmitted by the sandfly Lutzomyia longipalpis, with wild canids and domestic dogs as its main reservoirs.In this context, PPAR± might be a possible candidate gene to contribute to the genetically determined risk of VL. In a case-control study conducted by our group in the endemic area of Teresina-PI genotypes containing the mutated 162V allele were significantly more frequent among individuals with VL than among all uninfected individuals (p = 0.007). In addition healthy individuals having at least one mutated 162V allele are nearly four times more likely to contract the disease than individuals who do not have the mutation (odds ratio 3.91 and confidence interval 1.38-11.07). The present project aims to use CRISPR-Cas9 technology for the generation of genetically modified macrophages to contain the human PPAR± gene L162V mutation for in vitro infection assays with Leishmania infantum as well as an overall analysis of the gene expression profile of the modified cells with the purpose of evaluating the role of the L162V allelic variant of the PPAR± gene in the establishment and development of Visceral Leishmaniasis. (AU)