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E6020 is a synthetic agonist of Toll‐like receptor‐4 (TLR4). The purpose of this study was to evaluate the effect of different doses of E6020‐SE on Trypanosoma cruzi‐specific immune responses and its ability to confer protection against acute lethal infection in mice. Forty female BALB/c were infected with 500 trypomastigotes of T cruzi H1 strain, divided into four groups (n = 10) and treated at 7‐ and 14‐day post‐infection (dpi) with different doses of E6020‐SE or PBS (control). Survival was followed for 51 days, mice were euthanized and hearts were collected to evaluate parasite burden, inflammation and fibrosis. We found significantly higher survival and lower parasite burdens in mice injected with E6020‐SE at all doses compared to the control group. However, E6020‐SE treatment did not significantly reduce cardiac inflammation or fibrosis. On the other hand, E6020‐SE modulated Th1 and Th2 cytokines, decreasing IFN‐γ and IL‐4 in a dose‐dependent manner after stimulation with parasite antigens. We conclude that E6020‐SE alone increased survival by decreasing cardiac parasite burdens in BALB/c mice acutely infected with T cruzi but failed to prevent cardiac damage. Our results suggest that for optimal protection, a vaccine antigen is necessary to balance and orient a protective immune response. [ABSTRACT FROM AUTHOR]

Summary: Trypanosoma cruzi 24 (Tc24) is a recently described B‐cell superantigen (BC‐SAg) expressed by all developmental stages of T. cruzi, the causative agent of Chagas disease. BC‐SAgs are immunoevasins that interfere with the catalytic response available to a subset of natural antibodies comprising the preimmune (innate) repertoire. Electrophilic modifications of BC‐SAgs facilitate the formation of highly energetic covalent reactions favouring B‐cell differentiation instead of B‐cell downregulation. Therefore, the aim of this study was to convert the inhibitory signals delivered to B‐cells with specificity for Tc24 into activating signals after conjugating electrophilic phosphonate groups to recombinant Tc24 (eTc24). Covalent immunization with eTc24 increased the binding affinity between eTc24 and naturally nucleophilic immunoglobulins with specificity for this BC‐SAg. Flow cytometric analyses demonstrated that eTc24 but not Tc24 or other electrophilically modified control proteins bound Tc24‐specific IgM+ B‐cells covalently. In addition, immunization of mice with eTc24 adjuvanted with ISA720 induced the production of catalytic responses specific for Tc24 compared to the abrogation of this response in mice immunized with Tc24/ISA720. eTc24‐immunized mice also produced IgMs that bound recombinant Tc24 compared to the binding observed for IgMs purified from non eTc24‐immunized controls. These data suggest that eTc24 immunization overrides the immunosuppressive properties of this BC‐SAg. [ABSTRACT FROM AUTHOR]