Development of Synthetic Glycobiomarkers for the Follow-Up of Chagas Disease Chemotherapy and Serological and Molecular Assays for Evaluation of Trypanosoma cruzi Infections in the U.S-Mexico Border
Abstract
Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, affects 7-8 million people worldwide. Lately, the disease has been spread to nonendemic countries and regions, like the U.S. and Europe. The disease can be divided into two phases: the acute and chronic phases, which continue for years or even decades. There are two available drugs for CD treatment: benznidazole (BNZ) and nifurtimox (NFX). These drugs are highly effective in the acute phase but less efficient in the chronic stage. Other limitations of these drugs are their toxicity, leading to serious adverse events and premature treatment termination. Newer clinical trial studies have suggested that lower doses of BZN could benefit patients and avoid toxic adverse events. If left untreated, the infection may escalate into chronic CD (CCD), a condition causing heart and gastrointestinal complications that could result in disabilities or death. The absence of widely accepted and standardized biomarkers (BMK) for early detection of therapeutic responses in CCD and diagnosis in certain countries presents a significant public health challenge. This situation not only imposes financial strains on public health agencies but also poses difficulties for researchers to discover new medications or treatment methods. Conventional serology (CS) tests, employing enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence (IIF) with epimastigote-derived antigens or whole parasites, are still being used to evaluate chemotherapy responses with BZN or NFX. However, negative seroconversion by the CS commonly takes 10-20 years. Therefore, there is an urgent need for new biomarkers (BMKs) for the early assessment of outcomes of CD chemotherapy. Moreover, more efficient BMKs for follow-up of treated CD patients are needed to develop new and more effective drugs. The mammal-dwelling infective trypomastigote form has a cell surface with a complex coat composed of glycosylphosphatidylinositol (GPI)-anchored glycoproteins, such as tGPI-mucins (tGPI-MUCs), trans-sialidases (TSs), and mucin-associated surface proteins (MASPs), encoded by multi-gene families. Moreover, glycoinositolphospholipids (GIPLs) containing α-galactopyranosyl and β-galactofuranosyl epitopes are absent in humans and, hence, highly immunogenic. High levels of Ch anti-α-Gal antibodies (Ch anti-α-Gal Abs) are, thus, produced in the acute and chronic phases of the disease. These Abs correlate with an active CD infection and can be used to assess chemotherapeutic outcomes following BZN treatment early. Here, we also explored the use of α-Gal glycotopes as antigens for accurate CD diagnosis, especially in supposedly nonendemic settings like the U.S.-Mexico Border. However, the molecular and immunological characterization of parasitic molecules that could serve as diagnostic or prognostic BMKs is complex, time-consuming, and requires large amounts of parasite material. Our recent studies showed that these challenges can be addressed through a bottom-up approach called reversed immunoglycomics. In a series of studies presented here, we explored the use of tGPI-MUCs and synthetic-galactopyranosyl (α-Galp) and β-galactofuranosyl (α-Galf) structures as potential BMKs for CD diagnosis and follow-up of chemotherapy.
Subject Area
Biology|Biomedical engineering|Biochemistry|Clinical psychology
Recommended Citation
Estêvão da Silva, Igor Leandro, "Development of Synthetic Glycobiomarkers for the Follow-Up of Chagas Disease Chemotherapy and Serological and Molecular Assays for Evaluation of Trypanosoma cruzi Infections in the U.S-Mexico Border" (2023). ETD Collection for University of Texas, El Paso. AAI30819168.
https://scholarworks.utep.edu/dissertations/AAI30819168