Redirection of the Immune Response to the Functional Catalytic Domain of the Cystein Proteinase Cruzipain Improves Protective Immunity againstTrypanosomacruziInfection

Abstract

Despite the strong immune responses elicited after natural infection with Trypanosoma cruzi or vaccination against it, parasite survival suggests that these responses are insufficient or inherently inadequate. T. cruzi contains a major cystein proteinase, cruzipain, which has a catalytic N-terminal domain and a C-terminal extension. Immunizations that employed recombinant cruzipain or its N- and C-terminal domains allowed evaluation of the ability of cruzipain to circumvent responses against the catalytic domain. This phenomenon is not a property of the parasite but of cruzipain itself, because recombinant cruzipain triggers a response similar to that of cruzipain during natural or experimental infection. Cruzipain is not the only antigen with a highly immunogenic region of unknown function that somehow protects an essential domain for parasite survival. However, our studies show that this can be reverted by using the N-terminal domain as a tailored immunogen able to redirect host responses to provide enhanced protection.

Tc52 Amino-Terminal-Domain DNA Carried by Attenuated Salmonella enterica Serovar Typhimurium Induces Protection against a Trypanosoma cruzi Lethal Challenge

“…Similarly, immunization with fulllength Cz triggers an immune response mostly directed against the C-term domain, which is poorly protective. In contrast, immunization with the N-term domain of Cz redirects the immune response to the protective domain, thereby enhancing protection (54). In the case of Tc52, immunization with DNA vectors delivered by attenuated Salmonella encoding full-length Tc52 or its N-term or C-term domain did not result in marked differences in protection, as for Cz.…”

“…Previously, we demonstrated that the N-term domain of cruzipain (Cz), the major cysteine protease of T. cruzi, is the enzymatic and protective domain of the enzyme (54). The C-term domain of Cz is immunodominant during natural infection, eliciting a high titer of specific antibodies.…”

Coadministration of cruzipain and GM-CSF DNAs, a new immunotherapeutic vaccine againstTrypanosoma cruziinfection

“…Considering that Cz is highly immunogenic in natural infection, 13,36 it is not surprising that nEmpty as well as SEmpty-treated mice showed specific IgG and activated lymphocytes. The humoral and cellular immune response is elicited against the native Cz present in the infecting parasites.…”

Strategy for the Development of Vaccines Against Chagas Disease

“…Different regions of recombinant proteins from a major T. cruzi cystein proteinase, cruzipain, were used to investigate the protective immunity in mice. The N-terminal domain as an immunogen with CpG-ODN as an adjuvant was able to direct the host with better protective immunity [41].…”