Exploratory studies on factors that affect outcomes of infections with Leishmania infantum in humans

Abstract

Visceral leishmaniasis (VL) is characterized by a "cytokine storm" and can be lethal if left untreated. Most infections with the etiologic agent are, however, asymptomatic. Malnutrition and co-infections with invasive helminths are known risk factors for VL. The current unhealthy human diet and the new concept of environmental enteric dysfunction (EED) justify reevaluating these factors. Serum protein N-glycan profiles affect their functions and are markers of socioeconomic status and of metabolic syndrome (MetS), an inflammatory disease associated with microbial translocation (MT). EED also courses with MT. Chronic immune activation subsequent to MT is associated with poor immune responses. In a cohort of controls or L. infantum-infected individuals from Teresina, Brazil, we observed that: a) VL patients produce inflammatory patterns of N-glycans in IgG Fcs; b) The transcriptome of peripheral blood leukocytes has signatures indicating that B cells functionally differ between individuals with active or cured VL or asymptomatic infections. We now hypothesize that: MetS and EED, common conditions in the cohort, are risk factors for VL; N-glycan profiles of serum proteins are associated with distinct outcomes of infections with L. infantum; noninvasive helminth infections protect humans against SMet and therefore against LV; B cell transcriptional profiles vary according to outcomes of infections with L. infantum. We have serum, feces, urine, and mRNA purified from B cells, and relevant data from the Teresina cohort. We will evaluate signatures of: MetS, EED, MT and inflammation, serum protein N-glycan profiles, and infections with non-invasive helminths. We will generate and analyze a transcriptome of B-cells. We will identify biomarkers for risk factors and for guiding diagnosis and interventions in VL and gather information that can help elucidate mechanisms of susceptibility to VL. (AU)