High-throughput analysis of dynamics of antibody responses against defined epitopes: prioritization of diagnostic and prognostic markers for Chagas disease

Institute/Research/Biotechnology Fdn, San Martin

Investigators

Abstract

1 PROJECT SUMMARY / ABSTRACT 2 3 Trypanosoma cruzi is a parasite responsible for an important human disease, Chagas Disease, which 4 is endemic in the Americas. The parasite is transmitted by the bite of an insect, or by blood transfusion 5 or organ transplants. Current treatment is limited to two nitro-heterocyclic drugs, which can cure the 6 disease in its acute phase, and provide benefits to patients in the chronic stage, but they have 7 unwanted adverse effects. New drugs and treatments are being explored, but certification of cure in 8 clinical trials is difficult to achieve. Management of this disease rests heavily on the use of diagnostic 9 tools: either molecular detection of parasite DNA by PCR or circulating antibodies against parasite 10 proteins or protein fragments. Detection of parasite DNA is difficult in the chronic stage of the disease 11 where parasitemia is low or undetectable, and hence requires serial blood sampling and PCR 12 replicates to achieve reliable detection. In contrast, serological assays readily detect infections, and 13 reduction in antibody levels (seroconversion or trend to seroconversion) have been historically used 14 as primary endpoints in clinical trials with some success but requiring long follow-ups of patients. A 15 major unmet need in this area is thus the ability to produce earlier informative outcomes for treatment 16 success or failure. This constitutes a major obstacle in current drug trials. For this, a constant stream 17 of new biomarkers is required to explore their potential at these tasks. One of the most promising 18 developments in the field was the construction of an Atlas of Antigens and Epitopes for Chagas 19 disease, providing extensive information on the seroprevalence of defined epitopes across diverse 20 populations of infected patients. Using a large set of antigens identified in this Atlas, we are beginning 21 to obtain valuable information on how individual antibody repertoires of patients in a clinical trial 22 respond to treatments. In this application we build on this previous work and propose to characterize 23 the dynamics of the human antibody response against this parasite. Using peptide microarrays 24 displaying selected Trypanosoma cruzi peptide antigens we will investigate these dynamics in an 25 expanded set of retrospective samples from diverse patient populations. We will use this information 26 to prioritize serology markers for applications seeking to monitor disease status or progression. With 27 this set of prioritized antigens, we will produce proof-of-principle immunoassays for use in clinical 28 settings.