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Title: | Cruzipain Sulfotopes-Specific Antibodies Generate Cardiac Tissue Abnormalities and Favor Trypanosoma cruzi Infection in the BALB/c Mice Model of Experimental Chagas Disease | Authors: | Soprano, Luciana L Ferrero, Maximiliano R Landoni, Malena García, Gabriela A Esteva, Monica I Couto, Alicia S Duschak, Vilma G |
Keywords: | C-T domain;Enfermedad de Chagas;Trypanosoma cruzi;cruzipain;cruzipain sulfotope-specific antibodies;immunopathogenesis | Issue Date: | 2021 | Journal: | Frontiers in cellular and infection microbiology | Abstract: | Trypanosoma cruzi cruzipain (Cz) bears a C-terminal domain (C-T) that contains sulfated epitopes "sulfotopes" (GlcNAc6S) on its unique N-glycosylation site. The effects of in vivo exposure to GlcNAc6S on heart tissue ultrastructure, immune responses, and along the outcome of infection by T. cruzi, 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-TIM) showed IgG2a/IgG1 <1, induced the production of cytokines from Th2, Th17, and Th1 profiles with respect to those of dC-TIM, which only induced IL-10 respect to the control mice. Surprisingly, after sublethal challenge, both C-TIM and dC-TIM showed significantly higher parasitemia and mortality than the control group. Second, mice exposed to BSA-GlcNAc6S as immunogen (BSA-GlcNAc6SIM) showed: severe ultrastructural cardiac alterations while BSA-GlcNAcIM conserved the regular tissue architecture with slight myofibril changes; a strong highly specific humoral-immune-response reproducing the IgG-isotype-profile obtained with C-TIM; and a significant memory-T-cell-response demonstrating sulfotope-immunodominance with respect to BSA-GlcNAcIM. After sublethal challenge, BSA-GlcNAc6SIM 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 T. cruzi, surprisingly reached higher parasitemias than control groups. These findings confirmed the indirect role of the sulfotopes, via their IgG-GlcNAc6S, both in the immunopathogenicity as well as favoring T. cruzi infection. |
Description: | Fil: Soprano, Luciana L. Area of Biochemistry of Proteins and Glycobiology of Parasites, Research Department, National Institute of Parasitology "Dr. Mario Fatala Chaben", ANLIS-Malbrán, Health Department; Buenos Aires, Argentina Fil: Ferrero, Maximiliano R. Area of Biochemistry of Proteins and Glycobiology of Parasites, Research Department, National Institute of Parasitology "Dr. Mario Fatala Chaben", ANLIS-Malbrán, Health Department; Buenos Aires, Argentina Fil: Landoni, Malena. Organic Chemistry Department, Natural and Exact Sciences Faculty; Research Center in Carbohydrates (CIHIDECAR), University of Buenos Aires; Buenos Aires, Argentina Fil: García, Gabriela A. Area of Biochemistry of Proteins and Glycobiology of Parasites, Research Department, National Institute of Parasitology "Dr. Mario Fatala Chaben", ANLIS-Malbrán, Health Department; Buenos Aires, Argentina Fil: Esteva, Mónica I. Area of Biochemistry of Proteins and Glycobiology of Parasites, Research Department, National Institute of Parasitology "Dr. Mario Fatala Chaben", ANLIS-Malbrán, Health Department; Buenos Aires, Argentina Fil: Couto, Alicia S. Organic Chemistry Department, Natural and Exact Sciences Faculty; Research Center in Carbohydrates (CIHIDECAR), University of Buenos Aires; Buenos Aires, Argentina Fil: Duschak, Vilma G. Area of Biochemistry of Proteins and Glycobiology of Parasites, Research Department, National Institute of Parasitology "Dr. Mario Fatala Chaben", ANLIS-Malbrán, Health Department; Buenos Aires, Argentina |
URI: | http://sgc.anlis.gob.ar/handle/123456789/2499 | DOI: | 10.3389/fcimb.2021.814276 |
Appears in Collections: | Artículos |
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