Genomic approaches to explore the consequences of the interaction of biologically distinct Leishmania infantum genotypes with vertebrate hosts and the impact on the epidemiology of the American Visceral Leishmaniasis

Abstract

Exploration of the genetic basis of visceral leishmaniasis (VL) has identified substantial amounts of biomarkers and thus has contributed to improve understanding of the pathogenesis of the VL. However, such findings have not been converted into disease control strategies. The identification of immunotherapeutic targets depends on the identification of metabolic pathways of the host, consistently associated with different phenotypes of responses. A genome-wide association study (GWAS) in an sample of dogs followed in a prospective cohortcould validate the genotype-phenotype associations previously identified by our group. The host response stratifications attributed to the genotypic variation of the parasite also represent a gap in this field. The evaluation of the clinical and immunological responses of dogs exposed to parasites with different genotypes could indicate if the variation of response previously observed in vitro is reflected in a subclinical infection in vivo, which would contribute to maintain the transmission cycle of the VL and, therefore, to evaluate the epidemiological impact of cocirculation of different genotypes of L. infantum. In addition, the identification of differently expressed genes in dogs exposed to different genotypes of the parasite could concomitantly indicate metabolic pathways with immunotherapeutic potential and validate candidate genes identified in the GWAS. Therefore, the purpose of this proposal is to validate genetic markers in an independent sample, to evaluate the association between canine response profiles and L. infantum genotypes, and to investigate the variation of gene expression in dogs exposed to different L. infantum genotypes. (AU)