AUTHOR=Soprano Luciana L. , Ferrero Maximiliano R. , Landoni Malena , García Gabriela A. , Esteva Mónica I. , Couto Alicia S. , Duschak Vilma G. 

TITLE=Cruzipain Sulfotopes-Specific Antibodies Generate Cardiac Tissue Abnormalities and Favor Trypanosoma cruzi Infection in the BALB/c Mice Model of Experimental Chagas Disease

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=11

YEAR=2022

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2021.814276

DOI=10.3389/fcimb.2021.814276

ISSN=2235-2988

ABSTRACT=<p><italic>Trypanosoma cruzi</italic> cruzipain (Cz) bears a C-terminal domain (C-T) that contains sulfated epitopes “sulfotopes” (GlcNAc6S) on its unique N-glycosylation site. The effects of <italic>in vivo</italic> exposure to GlcNAc6S on heart tissue ultrastructure, immune responses, and along the outcome of infection by <italic>T. cruzi</italic>, were evaluated in a murine experimental model, BALB/c, using three independent strategies. First, mice were pre-exposed to C-T by immunization. C-T-immunized mice (C-T<sub>IM</sub>) showed IgG2a/IgG1 &lt;1, induced the production of cytokines from Th2, Th17, and Th1 profiles with respect to those of dC-T<sub>IM</sub>, which only induced IL-10 respect to the control mice. Surprisingly, after sublethal challenge, both C-T<sub>IM</sub> and dC-T<sub>IM</sub> showed significantly higher parasitemia and mortality than the control group. Second, mice exposed to BSA-GlcNAc6S as immunogen (BSA-GlcNAc6S<sub>IM</sub>) showed: severe ultrastructural cardiac alterations while BSA-GlcNAc<sub>IM</sub> conserved the regular tissue architecture with slight myofibril changes; a strong highly specific humoral-immune-response reproducing the IgG-isotype-profile obtained with C-T<sub>IM</sub>; and a significant memory-T-cell-response demonstrating sulfotope-immunodominance with respect to BSA-GlcNAc<sub>IM</sub>. After sublethal challenge, BSA-GlcNAc6S<sub>IM</sub> showed exacerbated parasitemias, despite elevated IFN-γ levels were registered. In both cases, the abrogation of ultrastructural alterations when using desulfated immunogens supported the direct involvement of sulfotopes and/or indirect effect through their specific antibodies, in the induction of tissue damage. Finally, a third strategy using a passive transference of sulfotope-specific antibodies (IgG-GlcNAc6S) showed the detrimental activity of IgG-GlcNAc6S on mice cardiac tissue, and mice treated with IgG-GlcNAc6S after a sublethal dose of <italic>T. cruzi</italic>, surprisingly reached higher parasitemias than control groups. These findings confirmed the indirect role of the sulfotopes, <italic>via</italic> their IgG-GlcNAc6S, both in the immunopathogenicity as well as favoring <italic>T. cruzi</italic> infection.</p>