While visceral leishmaniasis (VL) presents high mortality if left untreated, most infections with the agent of the disease, Leishmania infantum, remain asymptomatic. The risk factors for developing VL are still not well known. VL is prevalent in middle and low-income populations and is characterized by a "cytokine storm". Inflammation affects IgG Fc N-glycosylation profiles, which, in turn, affect antibody effector functions. Indeed, VL patients produce IgGs with patterns of Fc N-glycans similar to those seen in inflammatory conditions. IgG Fc N-glycans also vary according to socio-economic status and with the markers for metabolic syndrome (MS), an inflammatory disease. Malnutrition is associated with susceptibility to VL, as are co-infections with invasive helminths. However, despite the current epidemiologic transition of diet, VL is still prevalent, warranting risk factors to be re-examined. Obesity, diet and inflammation are associated with susceptibility to infectious diseases and poor responses to vaccination. We thus hypothesize that: a) obesity and MS are risk factors for humans to develop VL because they affect the N-glycan profiles of IgG; b) N-glycan profiles of plasma proteins are associated with outcomes of infections with L. infantum; c) infestations of humans with non-invasive helminths (NIH) may protect them against MS, and thus also protect against VL. We will assess in asymptomatic infections, active disease, before and after treatment, and in healthy individuals from endemic and a non-endemic areas in Brazil: a) signatures of the total serum N-glycome in clinical parameters of VL and infections in general with L. infantum; b) markers of inflammation, MS and infections with NIH; c) their respective association with clinical outcomes of infections with L. infantum. We expect to obtain: a) biomarkers for early diagnosis and patient stratification; b) insights for novel therapeutic strategies and mechanisms of pathogenesis in VL.
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