Date Published: November 20, 2014
Publisher: Public Library of Science
Author(s): Núria Gironès, Sofía Carbajosa, Néstor A. Guerrero, Cristina Poveda, Carlos Chillón-Marinas, Manuel Fresno, Herbert B. Tanowitz. http://doi.org/10.1371/journal.pntd.0003337
Abstract: Chagas disease is caused by Trypanosoma cruzi infection, being cardiomyopathy the more frequent manifestation. New chemotherapeutic drugs are needed but there are no good biomarkers for monitoring treatment efficacy. There is growing evidence linking immune response and metabolism in inflammatory processes and specifically in Chagas disease. Thus, some metabolites are able to enhance and/or inhibit the immune response. Metabolite levels found in the host during an ongoing infection could provide valuable information on the pathogenesis and/or identify deregulated metabolic pathway that can be potential candidates for treatment and being potential specific biomarkers of the disease. To gain more insight into those aspects in Chagas disease, we performed an unprecedented metabolomic analysis in heart and plasma of mice infected with T. cruzi. Many metabolic pathways were profoundly affected by T. cruzi infection, such as glucose uptake, sorbitol pathway, fatty acid and phospholipid synthesis that were increased in heart tissue but decreased in plasma. Tricarboxylic acid cycle was decreased in heart tissue and plasma whereas reactive oxygen species production and uric acid formation were also deeply increased in infected hearts suggesting a stressful condition in the heart. While specific metabolites allantoin, kynurenine and p-cresol sulfate, resulting from nucleotide, tryptophan and phenylalanine/tyrosine metabolism, respectively, were increased in heart tissue and also in plasma. These results provide new valuable information on the pathogenesis of acute Chagas disease, unravel several new metabolic pathways susceptible of clinical management and identify metabolites useful as potential specific biomarkers for monitoring treatment and clinical severity in patients.
Partial Text: Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects approximately 8 million people worldwide  and kills more than 15,000 each year, thus representing a major cause of morbidity and mortality in endemic countries . Chagasic cardiomyopathy is the most serious and frequent manifestation in T. cruzi infected patients in the chronic phase of the disease. Acute Chagas disease is an often nonspecific and frequently unrecognized condition, but acute infection associated to congenital cases and oral transmission can have a fatal outcome in humans . Myocarditis, although uncommonly reported and difficult to diagnose, is uniformly present during acute infection. Moreover, endomyocardial biopsies taken when patients are diagnosed during this phase of the disease consistently reveal acute myocarditis, even if the patient is asymptomatic . The ranges of acute cardiac pathogenesis are characterized by pericardial effusion, pericarditis, ventricular enlargement with dysfunction or congestive heart failure or both . In the chronic phase, myocardial inflammation associated to mononuclear infiltrate is a common finding in histological sections, although the spatial association between parasites and inflammatory infiltrate is controversial and manifests as heart failure, arrhythmia, heart block, thromboembolism, stroke, and sudden death. Chronic Chagasic Cardiomyopathy is characterized by its severity, as well as by a worse prognosis when compared with other cardiomyopathies .
Chagas is a complex disease with acute and chronic phases showing cardiac alterations. Although, the immunopathogenesis is relatively well established, there are still several issues poorly understood. Among those: why a minority of asymptomatic patients become symptomatic after several years?; and which is the reason for the different clinical manifestations?. Besides, few drugs are available to date, which present adverse effects that many patients cannot tolerate. Thus, new drugs are urgently needed, and to achieve that, a deeper knowledge of clinical pathophysiology is required. In this respect, metabolomics may help to better characterize the pathophysiology of the disease as well as to define new biomarkers.