Post-translational modifications in Chagas Disease biological processes and diagnostics: novel methodological approaches and biological applications

Abstract

Chagas Disease, caused by the protozoan parasite T. cruzi, is a neglected disease, which can lead to Cardiomyopathy, neurological complications and megaviscera. Over 100 years after its description, this disease affects 8 million people and most of them do not know that they are infected. Although endemic in the South America, it has been recognized a worldwide public health problem due to global population migration. Despite the great efforts to control T. cruzi transmission and introduce novel therapeutic options, one of the unmet needs is the development of novel sensitive and specific diagnostic markers for treatment response and disease progression. Moreover, a better understanding of the T. cruzi-host interaction will aid in prioritize novel therapeutic targets. This project is divided in three parts: 1) analytical method development for post-translational modifications (PTMs); 2) elucidation of the role of protein glycosylation and arginylation in the T. cruzi-host interaction and 3) biomarker discovery for Chagas Disease. The development of novel analytical methods for PTMs analysis will offer the possibility to detect protein modifications in complex biological systems with high accuracy and sensitivity. In particular, the identification of protein glycosylation of different T. cruzi strains belonging to the seven DTUs will be evaluated and associated to the expression of specific glycosyltransferases. The large-scale analysis of the cell surface glycoproteome and glycome combined with functional assays will be used as a molecular determinant to link the T. cruzi glycosylation enzymes expression and phenotype. The characterization of protein arginylation in T. cruzi and the Tc-Ate1 enzyme involved in this process will allow us to understand the role of this poorly explored PTM in Chagas Disease biology. The third part of the project will be focused on implementing a diagnostic platform for urinary protein biomarker discovery in Chagas Disease. (AU)