Characterization of resistance and susceptibility genes in Visceral Leishmaniasis

Abstract

Leishmaniasis is a parasitic disease considered one of the main global public health problems. They are characterized by presenting a range of cutaneous, mucocutaneous and visceral clinical symptoms that are determined by the species of the parasite, and nutritional, genetic, and immunological aspects of the individual. Visceral leishmaniasis (VL), which results from infection with Leishmania infantum or Leishmania donovani, is the most serious clinical form and almost always fatal if untreated. Patients with symptomatic VL have high levels of anti-inflammatory mediators, with a predominance of IL-10 and reduced levels of IFN-g and TNF, which often culminate in tissue damage and cause kidney, liver, and splenic damage. However, most individuals develop subclinical symptoms and are considered asymptomatic. These individuals may have a cellular response to Leishmania antigens (Montenegro test positive), but without any symptoms; or they can be characterized as endemic controls - they do not show symptoms or cellular response to parasite antigens. It is known that the genetic basis that regulates the individual's immune response as a result of the Leishmania-host interaction plays an important role in resistance or susceptibility to VL, determining the profile of produced immune system mediators that direct the development of protective immunity or not during infection. The analysis of global gene expression in peripheral blood cells of individuals with VL, before and after treatment, as well as in asymptomatic individuals and endemic controls, showed alterations in the expression levels of several genes of the immune response. This analysis allows the understanding of new effectors of the immune response that may play an important role in the control of L. infantum infection in naturally infected hosts, in addition to providing new therapeutic and/or prophylactic targets against VL. Therefore, the aim of this project is to evaluate and validate the role of differentially expressed genes in samples from this cohort of patients in experimental models. For this, human lineage cells will be used for gene editing and analysis of cellular response during infection by L. infantum. In addition, the murine variants of selected genes will be used as a basis for the generation of mice genetically deficient for the genes of interest, which will be used to develop experimental models. The data generated in this project will be able to describe new pathways of the immune response as well as new effectors that act in the control of the infection by L. infantum. (AU)