T. cruzi immune evasion factors and vaccine design

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DESCRIPTION (provided by applicant): As with other pathogens that establish chronic infections, immune evasion strategies of Trypanosoma cruzi likely contribute to the failure of the host to control and clear the infection. The identification and characterization of virulence factors involved in inducing immune dysregulation and evasion should lead to critical targets for the development of vaccines and improved chemotherapeutics. This study focuses on T. cruzi proline racemase (TcPRAC), which is secreted by vertebrate stage parasites and is a polyclonal B cell activator. This study will test the hypothesis that the immunization with sub- mitogenic doses of TcPRAC will result in neutralization of the mitogenic activity and improve early pathogen-specific responses to other vaccine candidates upon challenge. To test the hypothesis that neutralization of TcPRAC polyclonal activation leads to improved humoral response to other target antigens, the efficacy of a vaccine combination of TcPRAC and the T. cruzi complement regulatory protein (CRP) will be evaluated in a challenge model. The T. cruzi CRP is a surface protein involved in evasion of the alternative and classical complement activation, thus facilitating early hematogenous spread of the parasites. Other studies have shown CRP to be an effective vaccine candidate, however non-specific polyclonal responses to parasite challenge delay antigen- specific responses to the CRP and other vaccine candidates, thus limiting the capacity of these vaccines to prevent or ameliorate the establishment of chronic disease. To test the hypothesis that neutralization of a parasite-derived mitogen can improve the efficacy of host immune responses, the following Specific Aims will be addressed: 1) Characterization of the mitogenic capacity of recombinant TcPRAC in vivo, determination of sub-mitogenic doses and analyze B cell subsets and the location of the polyclonal response; 2) Analysis of the protective capacity of sub-mitogenic doses of TcPRAC in an in vivo T. cruzi challenge model; 3) Test the efficacy a TcPRAC and CRP vaccine combination. The novel attempt to alter the immune dysregulation induced by the T. cruzi mitogen by immunologic neutralization may enhance the efficacy of other vaccine candidates in this model and may offer a general approach to vaccine design for other pathogens that induce polyclonal responses. Relevance: The goals of this research is to advance development of a vaccine for Chagas' disease. Chagas' disease currently afflicts 20 million people in Latin America and another 90 million people are at risk of infection with Trypanosoma cruzi, the causative agent. No vaccine is currently available to prevent or treat Chagas' disease and the proposed studies will test two vaccine candidates in experimental models.