The Role of IgG Fc N-Glycosylation on the Pathogenesis of Visceral Leishmaniasis: Insights Into New Strategies of Therapy

Abstract

Visceral leishmaniasis (VL) may be fatal if not treated and although hypergammaglobulinemia is a hallmark of VL, the contribution of antibodies in progression of disease remains unknown. Effector and regulatory functions of antibodies rely on their interactions with type I and II Fc receptors and these interactions are tuned by the patterns of antibody Fc N-glycosylation. Recently, we showed that in comparison healthy individuals, the overall IgG Fc N-glycan profiles are profoundly altered in VL patients, and together with serum regulators of immune responses (cytokines and C-reactive protein) we demonstrated the ability of IgG Fc glyco features to predict disease severity in VL patients. Importantly, we showed that Fc N-glycosylation profiles changes after treatment of VL. To uncover the potential role of IgG Fc glyco features on the pathogenesis of VL and the mechanisms that participate in those alterations, (i) we will evaluate the gene expression of B cells isolated from patients stratified into categories of disease severity, and associate it with IgG titers and profiles of Fc N-glycosylation; (ii) based on the knowledge raised by our work with VL patients, we will test the viability and efficacy of new strategies of therapy in an experimental model of progressive VL (hamsters). We will evaluate the effects of treatment of L. infantum chagasi-chronically infected hamsters with intravenous immunoglobulin (IVIG) preparations enriched with sialic acid, and in vivo enzymatic deglycosylation of IgG Fc. Thus, we expect to obtain insights into the mechanisms that IgG Fc glyco features influence progression and severity of VL and to innovate the treatment of the disease.