Dissecting the pathogenesis of Chagas Disease by deep glycomics and glycoproteomics approaches

• Grant number: 17/04032-5
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): August 01, 2019
• Effective date (End): December 31, 2021
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal researcher: Giuseppe Palmisano
• Grantee: Simon Ngao Mule
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Trypanosoma cruzi, the etiological agent of Chagas Disease or American trypanosomiasis, is highly heterogenetic, with multiple genotypes and phenotypes currently recognized. At present, T. cruzi is classified into six Discrete Typing Units (DTUs), TcI-TcVI, infecting humans along with the TcVII, which infects bats. Each DTU/genetic subdivision has a distinct biological and host association, clinical outcomes, pathogenicity and genotype. This genotypic and phenotypic heterogeneity is associated to different clinical presentations of Chagas Disease, such as disease progression, drug susceptibility and transmission cycles. While it has been demonstrated that there is an association between T. cruzi morphology, virulence and pathogenicity, the glycoproteome-pathogenicity relationship has not been established. Glycoproteins play key roles in vector-parasite-host interaction during the intricate life cycle of T. cruzi. The rationale of the proposed study is based on findings from a recent glycoproteomic-centric study published by our group that showed the stage-specific modulation of T. cruzi glycoproteome. The present project offers a platform to explore in detail the fine structure and functions of the glycoproteome of different virulent and avirulent T. cruzi strains and correlate the glycoproteome to the clinical and biological characteristics of T. cruzi. The aims of this project are: 1) characterize the N- and O-glycoproteome of a range of T. cruzi strains with varying degrees of virulence and drug resistance. This objective will be achieved by exploiting state-of-the-art LC-MS/MS instrumentation established in Professor Palmisano's laboratory. This analysis will be complemented by a deep glycomics analysis that will be performed in the laboratory of Prof. Morten Thaysen-Andersen at Macquarie University, Sydney, Australia; 2) correlate the glycoproteome profiles/signatures and the pathogenicity and virulence of the different T. cruzi strains representative of the six T. cruzi DTUs and other closely related trypanosomatids. Glycoproteome analysis of the existing T. cruzi DTUs are missing, and it is unknown whether the glycosylation of the surface proteins have an impact on the pathogenicity of T. cruzi parasites; 3) expand the knowledgebase of T. cruzi glycoproteins, which form potential therapeutic targets against Chagas Disease. The mass spectrometry-based data will be complemented with lectin array and immunoblotting analyses that will shed new lights on the strain-specific variety of T. cruzi glycosylation. The knowledge gained from this mass spectrometry-based glycoproteomics study will elucidate the glycoproteome-pathogenicity relationship, which will have a profound impact on the current phylogenetic knowledge and expand our understanding of the importance of protein glycosylation in the pathogenicity of T. cruzi. (AU)

Scientific publications

(9)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

COUTINHO, JOAO V. P.; ROSA-FERNANDES, LIVIA; MULE, SIMON NGAO; DE OLIVEIRA, GILBERTO SANTOS; MANCHOLA, NUBIA CAROLINA; SANTIAGO, VERONICA FEIJOLI; COLLI, WALTER; WRENGER, CARSTEN; MANSO ALVES, MARIA JULIA; PALMISANO, GIUSEPPE. The thermal proteome stability profile of Trypanosoma cruzi in epimastigote and trypomastigote life stages. JOURNAL OF PROTEOMICS, v. 248, SEP 30 2021. Web of Science Citations: 0.

MULE, SIMON NGAO; ROSA-FERNANDES, LIVIA; COUTINHO, JOAO V. P.; GOMES, VINICIUS DE MORAIS; MACEDO-DA-SILVA, JANAINA; SANTIAGO, VERONICA FEIJOLI; QUINA, DANIEL; DE OLIVEIRA, GILBERTO SANTOS; THAYSEN-ANDERSEN, MORTEN; LARSEN, MARTIN R.; LABRIOLA, LETICIA; PALMISANO, GIUSEPPE. Systems-wide analysis of glycoprotein conformational changes by limited deglycosylation assay. JOURNAL OF PROTEOMICS, v. 248, SEP 30 2021. Web of Science Citations: 0.

MULE, SIMON NGAO; GOMES, VINICIUS DE MORAIS; WAILEMANN, ROSANGELA A. M.; MACEDO-DA-SILVA, JANAINA; ROSA-FERNANDES, LIVIA; LARSEN, MARTIN R.; LABRIOLA, LETICIA; PALMISANO, GIUSEPPE. HSPB1 influences mitochondrial respiration in ER-stressed beta cells. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, v. 1869, n. 9 SEP 2021. Web of Science Citations: 0.

CAVALCANTE, TAINA; MEDEIROS, MARIANA MEDINA; MULE, SIMON NGAO; PALMISANO, GIUSEPPE; STOLF, BEATRIZ SIMONSEN. The Role of Sialic Acids in the Establishment of Infections by Pathogens, With Special Focus on Leishmania. FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, v. 11, MAY 13 2021. Web of Science Citations: 0.

MULE, SIMON NGAO; COSTA-MARTINS, ANDRE GUILHERME; ROSA-FERNANDES, LIVIA; DE OLIVEIRA, GILBERTO SANTOS; RODRIGUES, CARLA MONADELI F.; QUINA, DANIEL; ROSEIN, GRAZIELLA E.; GERALDES TEIXEIRA, MARTA MARIA; PALMISANO, GIUSEPPE. PhyloQuant approach provides insights into Trypanosoma cruzi evolution using a systems-wide mass spectrometry-based quantitative protein profile. COMMUNICATIONS BIOLOGY, v. 4, n. 1 MAR 11 2021. Web of Science Citations: 0.

LATROFA, MARIA STEFANIA; PALMISANO, GIUSEPPE; ANNOSCIA, GIADA; PIERRI, CIRO LEONARDO; CHANDRASHEKAR, RAMASWAMY; OTRANTO, DOMENICO. Major antigen and paramyosin proteins as candidate biomarkers for serodiagnosis of canine infection by zoonotic Onchocerca lupi. PLoS Neglected Tropical Diseases, v. 15, n. 2 FEB 2021. Web of Science Citations: 1.

MULE, S. N.; MANCHOLA, N. C.; DE OLIVEIRA, G. S.; PEREIRA, M.; MAGALHAES, R. D. M.; TEIXEIRA, A. A.; COLLI, W.; ALVES, M. J. M.; PALMISANO, G. Proteome-wide modulation of S-nitrosylation in Trypanosoma cruzi trypomastigotes upon interaction with the host extracellular matrix. JOURNAL OF PROTEOMICS, v. 231, JAN 16 2021. Web of Science Citations: 0.

MULE, SIMON NGAO; SAAD, JOYCE SILVA; FERNANDES, LIVIA ROSA; STOLF, BEATRIZ S.; CORTEZ, MAURO; PALMISANO, GIUSEPPE. Protein glycosylation inLeishmaniaspp.. MOLECULAR OMICS, v. 16, n. 5, p. 407-424, OCT 1 2020. Web of Science Citations: 0.

CAPELLI-PEIXOTO, JANAINA; MULE, SIMON NGAO; TANO, FABIA TOMIE; PALMISANO, GIUSEPPE; STOLF, BEATRIZ SIMONSEN. Proteomics and Leishmaniasis: Potential Clinical Applications. PROTEOMICS CLINICAL APPLICATIONS, v. 13, n. 6 AUG 2019. Web of Science Citations: 0.