| Grant number: | 21/07283-4 |
| Support Opportunities: | Regular Research Grants |
| Start date: | November 01, 2021 |
| End date: | October 31, 2023 |
| Field of knowledge: | Agronomical Sciences - Veterinary Medicine - Preventive Veterinary Medicine |
| Principal Investigator: | Valéria Marçal Felix de Lima |
| Grantee: | Valéria Marçal Felix de Lima |
| Host Institution: | Faculdade de Medicina Veterinária (FMVA). Universidade Estadual Paulista (UNESP). Campus de Araçatuba. Araçatuba , SP, Brazil |
Abstract
Domestic dogs are the main urban reservoir of Leishmania infantum, the causative agent of Visceral Leishmaniasis (VL) in the Americas. In VL endemic regions, the number of cases in humans is associated with the rate of canine infection. Currently available drugs are not efficient in the treatment of Canine Leishmaniasis (CanL) and months after treatment, most dogs present disease relapses, indicating the need to develop new drugs or new therapeutic strategies. In CanL, sick dogs mount an inefficient cellular immune response (Th1) to fight the parasite concomitant with an increase in the 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 infection. MiR194 has its expression increased in blood mononuclear cells of dogs with leishmaniasis and was correlated with an increase in the parasite load, whereas miR-150 has its expression decreased. miR-194 and miR-150 are involved in the regulation of genes related to the immune response. Among the target genes of miR-194, the MAPK1 gene is involved in the regulation of transcription factors T-bet related to the Th1 response, GATA3 to the Th2 response and FoxP3 in Treg cells, the SOCS2 gene negatively regulates the expression of Th1 cytokines (TNF-± and IFN-y) and Th2 (IL-4 and IL-10), and the TRAF6 gene, negatively regulates the expression of pro-inflammatory cytokines (IL-1, IL-6, TNF-± and TGF-²) , in addition to the expression of iNOS. The in silico analysis showed that miR-150 may be involved in the pathways regulating the targets TNF-±, Granzyme B (GZMB), Signal transducer and activator of transcription-1 (STAT1) and histone deacetylases 8 (HDAC8), ensuring greater survival of L. infantum in cells, and this has not yet been investigated. Therefore, molecular tools will be used to increase or decrease miR194 miR150 and their targets with immunoregulatory function will be evaluated. Better knowledge of the molecular mechanisms by which the parasite is able to evade the host's immune response may make it possible to identify future therapeutic targets for the treatment of CanL. (AU)
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