Input of NAcGlc6SO3 epitopes (sulfotopes) present in Trypanosoma cruzi glycoproteins, and their specific antibodies, in the infection and immune pathogenesis of experimental Chagas disease

L.L. SOPRANO ; M.R. FERRERO ; M.L. OLGIATI; M. LANDONI; G.A. GARCÍA; M.I. ESTEVA; A.S. COUTO; V.G. DUSCHAK.

Buenos Aires

Congreso; 18th International Congress of Infectious diseases; 2018

International Society for Infectious Diseases

Background: Trypanosoma cruzi, the causative agent of Chagasdisease contains a major antigen, cruzipain (Cz). The C-terminaldomain (C-T) of this glycoprotein bears N-linked high mannosetype sulfated oligosaccharide chains and is responsible for mostantibodies in natural and experimental infections. Mice immunizationwith C-T has shown that sulfate moieties of Cz molecule aretargets for specific immune responses and responsible for cardiacultrastructural abnormalities in absence of infection.Methods & Materials: After the molecular characterization ofthese sufotopes, BALB/c mice were immunized with Cz/C-T, priorand after desulfation treatment, and with NAcGlc6SO3-BSA, to befurther sublethally challenged with trypomastigotes to investigatewhether they are involved in immunepathogenesis and/or infectionof experimental Chagas disease.Results: C-T-immunized mice showed low IL-4 levels and elevatedIFN- concentration by capture ELISA using C-T as stimulusand a cytokines profile compatible with a mixed response showing:Th2 tendency with excessively high IFN and raised IL-17levels. By contrast, dC-T-immunized-mice presented undetectableIL-4 levels, low IFN- level and a cytokines profile like that ofcontrol but with a significantly elevated IL-10 value. In addition,ultrastructural cardiac alterations and main immunorecognition offibrils and mitochondria were observed in C-T-immunized miceboth confronted with polyclonal anti-Cz and myosin adsorbed anti-Cz sera. After sublethal challenge, elevated parasitaemias wereobserved. Mortality was 20 and 80% in C-T and dC-T immunizedmice, respectively and mice from dC-T group that survivedpresented severe muscle alterations. BSA-NAcGlc6SO3-immunizedmice mounted a predominant IgG1and IgG2b immune responsefollowed by IgG2a, demonstrating the immunodominance of thesulfotope and a vigorous mice memory T cells response, similarlyto C-T-immunized mice. After sublethal infection, mice immunizedwith the sulfotope displayed excessively elevated parasitemias,similar IFN-levels and significant lower mortality percentage thanthose from BSA-NAcGlc control group. Furthermore, mice treatedby passive transference of sulfate-specific IgGs purified from seraof BSA-NAcGlc6SO3-immunized mice, exhibited ultrastructuralalterations in cardiac tissue. After challenge, those treated withsulfate-specific IgGs presented higher parasitemias than controlsConclusion: Altogether, these findings have demonstrated thatsulfotopes and their specific antibodies display a dual role, participatingin the host-tissue immunopathogenicity of experimentalChagas disease and favoring the infection by T. cruzi.