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. FERRERO; M. L. OLGIATI; M. LANDONI; G. A. GARCIA; M. I. ESTEVA; A. S. COUTO; V G DUSCHAK

Buenos Aires

Congreso; 18th International Congress on Infectius Daseases; 2018

International Society for Infectious diseases

Trypanosoma cruzi, the causative agent of Chagas disease contains a major antigen, cruzipain (Cz). The C-terminal domain (C-T) of this glycoprotein bears N-linked high mannose type sulfated oligosaccharide chains and is responsible for most antibodies in natural and experimental infections. Mice immunization with C-T has shown that sulfate moieties of Cz molecule are targets for specific immune responses and responsible for cardiac ultrastructural abnormalities in absence of infection. After the molecular characterization of these sufotopes, BALB/c mice were immunized with Cz/C-T, prior and after desulfation treatment, and with NAcGlc6SO3-BSA, to be further sublethally challenged with trypomastigotes to investigate whether they are involved in immunepathogenesis and/or infection of experimental Chagas disease. C-T-immunized mice showed low IL-4 levels and elevated IFN-γ concentration by capture ELISA using C-T as stimulus and a cytokines profile compatible with a mixed response showing: Th2 tendency with excessively high IFNγ and raised IL-17 levels. By contrast, dC-T-immunized-mice presented undetectable IL-4 levels, low IFN-γ level and a cytokines profile like that of control but with a significantly elevated IL-10 value. In addition, ultrastructural cardiac alterations and main immunorecognition of fibrils and mitochondria were observed in C-T-immunized mice both confronted with polyclonal anti-Cz and myosin adsorbed anti-Cz sera. After sublethal challenge, elevated parasitaemias were observed. Mortality was 20 and 80 % in C-T and dC-T immunized mice, respectively and mice from dC-T group that survived presented severe muscle alterations. BSA-NAcGlc6SO3-immunized mice mounted a predominant IgG1and IgG2b immune response followed by IgG2a, demonstrating the immunodominance of the sulfotope and a vigorous mice memory T cells response, similarly to C-T-immunized mice. After sublethal infection, mice immunized with the sulfotope displayed excessively elevated parasitemias, similar IFN-γ levels and significant lower mortality percentage than those from BSA-NAcGlc control group. Furthermore, mice treated by passive transference of sulfate-specific IgGs purified from sera of BSA-NAcGlc6SO3-immunized mice, exhibited ultrastructural alterations in cardiac tissue. After challenge, those treated with sulfate-specific IgGs presented higher parasitemias than controls. Altogether, these findings have demonstrated that sulfotopes and their specific antibodies display a dual role, participating in the host-tissue immunopathogenicity of experimental Chagas disease and favoring the infection by T. cruzi.