Antigen presentation during Trypanosoma cruzi infection: in search of a new effective vaccine

PROJECT SUMMARY/ABSTRACT Chagas disease, caused by the parasite Trypanosoma cruzi, is a significant global health concern, primarily affecting Latin America but also impacting regions in Europe and the US. Currently, there are limited treatment options available, and no vaccines have been developed. The long-term objective of this project aims to address the difficulties associated with vaccine development for Chagas disease, by investigating the adaptive immune response against T. cruzi and by exploring innovative immunization strategies first in mice, but with the ultimate goal of developing effective vaccines that can be translated to dogs and humans. The research will focus on enhancing CD8+ T cell responses, as well as promoting Th1 and antibody responses, which are critical for controlling the infection. The specific aims of this proposal start with an exhaustive analysis of the peptide repertoire presented in MHC molecules of dendritic cells (DCs) during infection, identifying not only key vaccine candidates, but also the antigen presentation pathways involved in generating the peptidome. Recent evidence published by our group shows a significant role of antigen cross-presentation (XPt) to elicit protective immune responses. Based on that premise, a collection of peptides preferentially generated by (but not limited to) antigen XPt will be selected. Various vaccination approaches will be evaluated with the selected peptides, including the targeting of multiple parasite antigens to endocytic receptors that are specifically expressed in DCs, like DNGR-1. The choice of the DNGR-1 receptor as targeting strategy is not trivial. Antigens following the DNGR-1 endocytic pathway will be preferentially cross-presented, but the presence of the adjuvant Poly (I:C) will also favor the priming of Th1-biased specific CD4+ T cell responses and antibody production. Thus, an immunization strategy based on targeting only one endocytic receptor, will likely induce several effectors of the adaptive immunity. Another crucial aspect is that DNGR-1 is also present in DCs of other domestic parasite reservoirs, including dogs and humans, indicating a high potential for translation to these species. This research will advance our understanding of Chagas disease and pave the way for effective vaccines to combat this global health issue. The results will provide insights into T. cruzi immunology and contribute to the broader field of vaccine development against parasitic diseases. Moreover, the project will build research capacity and expertise in the host country, fostering scientific progress and addressing a pressing health issue.