A Trypanosoma cruzi Antigen and Epitope Atlas: deep characterization of antibody specificities in Chagas Disease patients across the Americas

During an infection, the immune system produces pathogen-specific antibodies. With time, these antibody repertoires become specific to the history of infections and represent a rich source of diagnostic markers. However, the specificities of these antibodies are mostly unknown. Here, using high-density peptide arrays we examined the specificities of human antibody repertoires of Chagas disease patients. Chagas disease is a neglected disease caused by Trypanosoma cruzi, a protozoan parasite that evades immune mediated elimination and mounts long-lasting chronic infections. We describe here the first proteome-wide search for antigens and epitopes and their seroprevalence at the individual level and across human populations. In a first discovery screening of 2.84 million short peptides spanning two T. cruzi proteomes we found 3,868 distinct antigenic protein regions. Further analysis of repertoires from 71 individuals provided information on their seroprevalence and showed a large fraction of private epitopes of low seroprevalence (<20%), and novel high seroprevalence antigens. Using single-residue mutagenesis we found the core epitopes required for antibody binding for 232 of these epitopes. These datasets enable the study of the Chagas antibody repertoire at an unprecedented depth and granularity, while also providing a rich source of novel serological biomarkers. IMPACT STATEMENTThis work reveals the diversity and extent of antibody specificities in Chagas Disease and provides a wealth of well-defined antigenic markers for diagnosis and development of serological applications for this neglected infectious disease.