TY - JOUR
T1 - Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in trypanosoma cruzi
AU - Shiratsubaki, Isabel S.
AU - Fang, Xin
AU - Souza, Rodolpho O.O.
AU - Palsson, Bernhard O.
AU - Silber, Ariel M.
AU - Siqueira-Neto, Jair L.
N1 - Funding Information: This research is supported by Microbial Science Initiative Graduate Research Fellowship (UCSD Center for Microbiome Innovation), Novo Nordisk Foundation Center for Biosustainability and the Technical University of Denmark (grant number NNF10CC1016517), Foundation for Research Support of the State of S?o Paulo (FAPESP) grants 2016 / 06034-2 to AMS and the joint grant to AMS and Prof. Michael Barrett (University of Glasgow) co-funded by MRC and FAPESP 2018/14432-3, Brazil National Council for Scientific and Technological Development (CNPq) grants 301971 / 2017-0 and 404769 / 2018-7, Research Council United Kingdom Global Challenges Research Fund under grant agreement ?A Global Network for Neglected Tropical Diseases? (grant MR/P027989/ 1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding Information: Funding:ThisresearchissupportedbyMicrobial ScienceInitiativeGraduateResearchFellowship (UCSDCenterforMicrobiomeInnovation),Novo NordiskFoundationCenterforBiosustainabilityand theTechnicalUniversityofDenmark(grantnumber NNF10CC1016517),FoundationforResearch SupportoftheStateofSãoPaulo(FAPESP)grants 2016/06034-2toAMSandthejointgranttoAMS andProf.MichaelBarrett(UniversityofGlasgow) co-fundedbyMRCandFAPESP2018/14432-3, BrazilNationalCouncilforScientificand TechnologicalDevelopment(CNPq)grants301971 /2017-0and404769/2018-7,ResearchCouncil UnitedKingdomGlobalChallengesResearchFund undergrantagreement“AGlobalNetworkfor NeglectedTropicalDiseases”(grantMR/P027989/ 1).Thefundershadnoroleinstudydesign,data collectionandanalysis,decisiontopublish,or preparationofthemanuscript. Publisher Copyright: © 2020 Shiratsubaki et al.
PY - 2020/10
Y1 - 2020/10
N2 - 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 (see S1–S4 GEMs). 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 hexoki-nase. 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 pre-dictions. 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 an in sil-ico GEM comparison among different stages in the T. cruzi life cycle.
AB - 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 (see S1–S4 GEMs). 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 hexoki-nase. 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 pre-dictions. 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 an in sil-ico GEM comparison among different stages in the T. cruzi life cycle.
UR - https://www.scopus.com/pages/publications/85093705966
U2 - 10.1371/journal.pntd.0008728
DO - 10.1371/journal.pntd.0008728
M3 - Article
C2 - 33021977
SN - 1935-2727
VL - 14
SP - 1
EP - 20
JO - PLoS Neglected Tropical Diseases
JF - PLoS Neglected Tropical Diseases
IS - 10
M1 - e0008728
ER -