Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi

Autor(es)

Shiratsubaki, Isabel S. ^{[1, 2]} ; Fang, Xin ^[2] ; Souza, Rodolpho O. O. ^[3] ; Palsson, Bernhard O. ^{[4, 2, 5]} ; Silber, Ariel M. ^[3] ; Siqueira-Neto, Jair L. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 - USA

^[2] Univ Calif San Diego, Dept Bioengn, La Jolla, CA - USA

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Lab Biochem Tryps LaBTryps, Sao Paulo, SP - Brazil

^[4] Tech Univ Denmark, Novo Nordisk Fdn Ctr Biosustainabil, Lyngby - Denmark

^[5] Univ Calif San Diego, Dept Pediat, La Jolla, CA - USA

• Tipo de documento: Artigo Científico
• Fonte: PLoS Neglected Tropical Diseases; v. 14, n. 10 OCT 2020.
• Citações Web of Science: 0

Resumo

Chagas disease is a neglected tropical disease and a leading cause of heart failure in Latin America caused by a protozoan called Trypanosoma cruzi. This parasite presents a complex multi-stage life cycle. Anti-Chagas drugs currently available are limited to benznidazole and nifurtimox, both with severe side effects. Thus, there is a need for alternative and more efficient drugs. Genome-scale metabolic models (GEMs) can accurately predict metabolic capabilities and aid in drug discovery in metabolic genes. This work developed an extended GEM, hereafter referred to as iIS312, of the published and validated T. cruzi core metabolism model. From iIS312, we then built three stage-specific models through transcriptomics data integration, and showed that epimastigotes present the most active metabolism among the stages (seeS1-S4GEMs). Stage-specific models predicted significant metabolic differences among stages, including variations in flux distribution in core metabolism. Moreover, the gene essentiality predictions suggest potential drug targets, among which some have been previously proven lethal, including glutamate dehydrogenase, glucokinase and hexokinase. To validate the models, we measured the activity of enzymes in the core metabolism of the parasite at different stages, and showed the results were consistent with model predictions. Our results represent a potential step forward towards the improvement of Chagas disease treatment. To our knowledge, these stage-specific models are the first GEMs built for the stages Amastigote and Trypomastigote. This work is also the first to present anin silico GEM comparison among different stages in the T. cruzi life cycle. (AU)

• Processo FAPESP: 16/06034-2 - O papel biológico de aminoácidos e seus metabólitos derivados em Trypanosoma cruzi
• Beneficiário: Ariel Mariano Silber
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/14432-3 - Uma rede para uma biologia integrativa em doenças negligenciadas: conectando a epigenética, o metabolismo e a biologia celular em tripanossomatídeos patogênicos
• Beneficiário: Ariel Mariano Silber
• Modalidade de apoio: Auxílio à Pesquisa - Temático