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

Isabel S Shiratsubaki,Rodolpho O O Souza,Jair L Siqueira-Neto,Xin Fang,Ariel M Silber,Bernhard O Palsson,Igor C Almeida

doi:10.1371/journal.pntd.0008728

Abstract

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 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 an in silico GEM comparison among different stages in the T. cruzi life cycle.

Highlights

Chagas disease is a neglected tropical disease affecting millions of people, especially in the Americas where it is endemic [1]
Chagas disease is caused by T. cruzi, a protozoan that can be transmitted through insect vectors
This study presents an extended Genome-scale metabolic models (GEMs) of T. cruzi, hereafter referred to as iIS312, of the published and validated T. cruzi CL Brener core metabolism model iSR215 [13]

Summary

Introduction

Chagas disease is a neglected tropical disease affecting millions of people, especially in the Americas where it is endemic [1]. Chagas disease presents two clinical phases during infection: acute, and chronic. The chronic phase is characterized by an undetectable parasitemia and a robust immune response in immunocompetent individuals. It most frequently presents an indeterminate asymptomatic form that can last for decades. In some patients it leads to a symptomatic form characterized by cardiac and/or digestive complications, which makes Chagas disease one of the leading causes of heart failure in the Americas. Current anti-Chagas drug options are limited to benznidazole and nifurtimox. Both drugs can cause severe gastrointestinal, dermatological, and neurological side effects, and are more efficient when the infected individual is treated during the acute phase. There is an urgent need for alternative and more efficient drugs

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Conclusion