Abstract
Chagas disease is caused by the parasite Trypanosoma cruzi, and it begins with a short acute phase characterized by high parasitemia followed by a life-long chronic phase with scarce parasitism. Cardiac involvement is the most prominent manifestation, as 30% of infected subjects will develop abnormal ventricular repolarization with myocarditis, fibrosis and cardiomyocyte hypertrophy by undefined mechanisms. Nevertheless, follow-up studies in chagasic patients, as well as studies with murine models, suggest that the intensity of clinical symptoms and pathophysiological events that occur during the acute phase of disease are associated with the severity of cardiac disease observed during the chronic phase. In the present study we investigated the role of microRNAs (miRNAs) in the disease progression in response to T. cruzi infection, as alterations in miRNA levels are known to be associated with many cardiovascular disorders. We screened 641 rodent miRNAs in heart samples of mice during an acute infection with the Colombiana T.cruzi strain and identified multiple miRNAs significantly altered upon infection. Seventeen miRNAs were found significantly deregulated in all three analyzed time points post infection. Among these, six miRNAs had their expression correlated with clinical parameters relevant to the disease, such as parasitemia and maximal heart rate-corrected QT (QTc) interval. Computational analyses identified that the gene targets for these six miRNAs were involved in networks and signaling pathways related to increased ventricular depolarization and repolarization times, important factors for QTc interval prolongation. The data presented here will guide further studies about the contribution of microRNAs to Chagas heart disease pathogenesis.
Highlights
Chagas disease is caused by the infection of an intracellular protozoan parasite, Trypanosoma cruzi, and affects 8 million individuals worldwide [1]
The life-long infection begins with a short acute phase, which is associated to parasites circulating in the bloodstream, tissue parasitism, and various signs and symptoms including those related to myocarditis
We describe for the first time the effect of acute T. cruzi infection on host miRNA expression by screening 641 rodent miRNAs in heart samples
Summary
Chagas disease is caused by the infection of an intracellular protozoan parasite, Trypanosoma cruzi, and affects 8 million individuals worldwide [1]. The acute phase of the disease is associated to parasites circulating in the bloodstream and intense tissue parasitism [2]. Patients with severe symptoms of acute Chagas disease present myocarditis, with myocardial dyskinesis, heart enlargement and heart failure [3]. Alterations in echocardiography (ECHO) and electrocardiography (ECG) such as disturbances of ventricular repolarization, pericardial effusion and atrial fibrillation during the acute phase of Chagas disease are associated with poor prognosis [4]. After resolution of the acute phase, chronically infected patients display sub patent parasitemia with low tissue parasitism and an asymptomatic (indeterminate) form of the disease. There is evidence that the intensity of symptoms in the acute phase may be positively correlated to the severity of the cardiac disease in the chronic phase [7,8]
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