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Reprogramming of Trypanosoma cruzi metabolism triggered by parasite interaction with the host cell extracellular matrix

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Mattos, Eliciane C. [1] ; Canuto, Gisele [2] ; Manchola, Nubia C. [1] ; Magalhaes, Rubens D. M. [3] ; Crozier, Thomas W. M. [4] ; Lamont, Douglas J. [5] ; Tavares, Marina F. M. [6] ; Colli, Walter [1] ; Ferguson, Michael A. J. [4] ; Alves, Maria Julia M. [1]
Número total de Autores: 10
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, Sao Paulo - Brazil
[2] Univ Fed Bahia, Inst Quim, Dept Quim Analit, Salvador, BA - Brazil
[3] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Biol Celular & Mol & Bioagentes Patogen, Ribeirao Preto - Brazil
[4] Univ Dundee, Sch Life Sci, Wellcome Ctr Antiinfect Res, Dundee - Scotland
[5] Univ Dundee, Sch Life Sci, Fingerprints Prote Facil, Dundee - Scotland
[6] Univ Sao Paulo, Inst Quim, Dept Quim Fundamental, Sao Paulo - Brazil
Número total de Afiliações: 6
Tipo de documento: Artigo Científico
Fonte: PLoS Neglected Tropical Diseases; v. 13, n. 2 FEB 2019.
Citações Web of Science: 1

Trypanosoma cruzi, the etiological agent of Chagas' disease, affects 8 million people predominantly living in socioeconomic underdeveloped areas. T. cruzi trypomastigotes (Ty), the classical infective stage, interact with the extracellular matrix (ECM), an obligatory step before invasion of almost all mammalian cells in different tissues. Here we have characterized the proteome and phosphoproteome of T. cruzi trypomastigotes upon interaction with ECM (MTy) and the data are available via ProteomeXchange with identifier PXD010970. Proteins involved with metabolic processes (such as the glycolytic pathway), kinases, flagellum and microtubule related proteins, transport-associated proteins and RNA/DNA binding elements are highly represented in the pool of proteins modified by phosphorylation. Further, important metabolic switches triggered by this interaction with ECM were indicated by decreases in the phosphorylation of hexokinase, phosphofructokinase, fructose-2,6-bisphosphatase, phosphoglucomutase, phosphoglycerate kinase in MTy. Concomitantly, a decrease in the pyruvate and lactate and an increase of glucose and succinate contents were detected by GC-MS. These observations led us to focus on the changes in the glycolytic pathway upon binding of the parasite to the ECM. Inhibition of hexokinase, pyruvate kinase and lactate dehydrogenase activities in MTy were observed and this correlated with the phosphorylation levels of the respective enzymes. Putative kinases involved in protein phosphorylation altered upon parasite incubation with ECM were suggested by in silico analysis. Taken together, our results show that in addition to cytoskeletal changes and protease activation, a reprogramming of the trypomastigote metabolism is triggered by the interaction of the parasite with the ECM prior to cell invasion and differentiation into amastigotes, the multiplicative intracellular stage of T. cruzi in the vertebrate host. Author summary Adhesion of Trypanosoma cruzi to distinct elements of ECM involving different surface proteins from the infective stage of the parasite has been described. Despite the relevance of ECM for T. cruzi infection, the signaling pathways triggered in trypomastigotes upon interactions with ECM are less well understood. In previous work we demonstrated the dephosphorylation of proteins, such as -tubulin, paraflagellar rod proteins and ERK 1/2 in trypomastigotes incubated with either laminin or fibronectin. Further, we described changes in the S-nitrosylation and nitration pattern of proteins from trypomastigote incubated with ECM. To expand our knowledge on ECM triggered parasite signaling we applied quantitative proteomic and phosphoproteomic studies to trypomastigotes incubated with ECM (MTy) compared to controls (Ty). Our results indicate relevant changes in total protein and phosphoprotein profiles in MTy. The kinases implicated in the modifications were suggested by bioinformatic analyses, as well as the number of modifications and the frequency of amino acids per peptide that have been modified. Proteins involved in metabolic processes, including enzymes from the glycolytic pathway, phosphatases and kinases were the most representative groups among the proteins modified by phosphorylation. Quantification of metabolites in MTy and Ty also indicated that glucose metabolism is impaired in trypomastigotes incubated with ECM. The significant inhibition of hexokinase, pyruvate kinase and lactate dehydrogenase activities in MTy associated with phosphorylation levels, strongly suggests that trypomastigotes reprogram their metabolism in response to interaction with the extracellular matrix, an obligatory step prior to host cell invasion. (AU)

Processo FAPESP: 18/03727-2 - Papel dos segundos mensageiros nas vias de sinalização envolvidas na interação de Trypanosoma cruzi e matriz extracelular
Beneficiário:Nubia Carolina Manchola Varón
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 13/16002-2 - Identificação de proteínas de flagelo de Trypanosoma Cruzi na resposta a adesão à matriz extracelular e ao citoesqueleto da célula hospedeira
Beneficiário:Eliciane Cevolani Mattos
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 14/25494-9 - Resposta de Trypanosoma cruzi ao meio ambiente: matriz extracelular e mudanças de pH
Beneficiário:Maria Julia Manso Alves
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 12/50188-3 - Adesão de tripomastigotas Trypanosoma Cruzi a matriz extracelular: modificações pós-traducionais de proteínas do parasita
Beneficiário:Maria Julia Manso Alves
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 16/14506-1 - Determinação do perfil antigênico humoral de pacientes chagásicos utilizando phage display de genoma de Trypanosoma Cruzi
Beneficiário:Walter Colli
Linha de fomento: Auxílio à Pesquisa - Regular