Dissecting the pathogenesis of Chagas disease by deep glycomics and glycoproteomics approaches.

Author(s)

Simon Ngao Mule

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2021-12-07

Examining board members

Giuseppe Palmisano; João Marcelo Pereira Alves; Carlos André Ornelas Ricart; Adriane Regina Todeschini

• Advisor: Giuseppe Palmisano

Abstract

Trypanosoma cruzi is a unicellular protozoan parasite responsible for the neglected tropical disease (NTD) termed Chagas disease (American Trypanosomiasis), a disease endemic in 21 South and Central American countries. Chagas disease is also an emerging global health concern with cases reported in Northern America, Europe, Japan, and Australia. The disease presents in variable clinical forms, and the treatment options available, Benznidazole and Nifurtimox are limited by high toxicities, side effects and decreasing treatment efficiency due to resistance by T. cruzi parasites. T. cruzi strains are genetically diverse, with implications on pathogenicity and virulence, disease progression and outcome, and drug susceptibility/resistance. In this thesis, the application of mass spectrometry to elucidate key T. cruzi molecular aspects will be presented, including: 1) system-wide modulation of the proteome between growth stages and between different parasite strains and species, and 2) modulation of T. cruzi posttranslational modifications (PTMs). For the proteomics part, A) the modulation of membrane proteins of T. cruzi CL14 strain during progression from exponential to stationary growth phases to elucidate the molecular changes during the early stages of metacyclogenesis, and B) the systems-wide protein expression profiles between T. cruzi strains and closely related trypanosome species will be presented. Analysis of PTMs by mass spectrometry will focus on: A) the modulation of T. cruzi trypomastigote protein S-nitrosylation following incubation with host extracellular matrix, B) the systems-wide analysis of glycoprotein conformational changes, and C) the mapping of intact N- and O-linked glycoproteomes and N- and O-glycomes, and their differential expression between T. cruzi strains and closely related trypanosome species. Taken together, this thesis shows the importance of proteomics in studying the molecular changes in protein expression and PTMs during host-pathogen interaction. Specifically, the methods developed and implemented in this thesis will be useful for the scientific community to study not only T. cruzi infections but also other biological systems. Finally, this thesis sheds new lights on the role of specific protein and PTMs targets for Chagas disease diagnostic and therapy. (AU)

• FAPESP's process: 17/04032-5 - Dissecting the pathogenesis of Chagas Disease by deep glycomics and glycoproteomics approaches
• Grantee: Simon Ngao Mule
• Support Opportunities: Scholarships in Brazil - Doctorate