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MiRNA 194 in the regulation of the immunological response of peripheral blood mononuclear cells in Canine Leishmaniasis

Grant number: 19/14894-0
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2020
Effective date (End): January 31, 2023
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal researcher:Valéria Marçal Felix de Lima
Grantee:Sidnei Ferro Costa
Home Institution: Faculdade de Medicina Veterinária (FMVA). Universidade Estadual Paulista (UNESP). Campus de Araçatuba. Araçatuba , SP, Brazil

Abstract

Domestic dogs are the major urban reservoirs of Leishmania infantum, the causative agent of Visceral Leishmaniasis (VL) in the Americas. In regions endemic for VL, the number of cases in humans is associated with the rate of canine infection. The drugs currently available are not efficient in the treatment of Canine Leishmaniasis (CanL) and months after treatment most dogs present recurrence of the disease, indicating the need for the development of new drugs or new therapeutic strategies. In CanL, diseased dogs assemble an ineffective cellular immune response (Th1) to combat the parasite concomitant with increased humoral immune response (Th2). MicroRNAs (miRNAs) are small, non-coding RNAs involved in the regulation of gene expression and translation of proteins involved in the regulation of the immune response. Several studies have demonstrated miRNAs as key regulators of cellular responses in Leishmania spp. infections. miR194 has increased expression in the blood of dogs with Leishmaniasis and has been correlated with increased parasite burden. MiR-194 is involved in the regulation of genes related to the immune response. Among the target genes, the MAPK1 gene is involved in the regulation of T-bet transcription factors related to Th1 response, GATA3 Th2 response and FoxP3 to Treg cells. The SOCS2 gene negatively regulates the expression of Th1 cytokines (TNF-± and IFN-³) and Th2 (IL-4 and IL-10). The TRAF6 gene negatively regulates the expression of proinflammatory cytokines (IL-1, IL-6, TNF-± and TGF-²) in addition to iNOS expression. Therefore, molecular tools will be used to increase or decrease miR194 and its functional role in the expression of transcription factors and cytokines related to Th1 and Th2 responses and the activation of leishmanicidal mechanisms in peripheral blood mononuclear cells and subsequently the correlation with the parasite load will be analyzed. The best knowledge of the molecular mechanisms by which the parasite can evade the immune response of the host may make it possible to identify future therapeutic targets for the treatment of CanL. (AU)