MicroRNA Transcriptome Profiling in Heart of Trypanosoma cruzi-Infected Mice: Parasitological and Cardiological Outcomes

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.

MicroRNAs: Biological Regulators in Pathogen–Host Interactions

“…The modulation of miRNAs from the hearts of T. cruzi-infected mice is positively correlated with a parasitemia peak at 30 days post-infection (dpi), as observed for miR-146b, miR-21, miR-142-3p, and miR-142-5p, while a negative correlation is observed for miR-145-5p and miR-149-5p and also suggests the regulation of genes involved in the pathophysiological conditions of experimental infection, such as calcium and potassium channels and electrocardiography (ECG) parameters [116], as shown in Figure 3. The dysregulation of miR-133 and miR-208 have been correlated with heart genes that are related to cardiovascular disease in chronic Chagas patients and acute T. cruzi-infected mice [112,114,115].…”

Dysregulated CD4+ T Cells and microRNAs in Myocarditis

“…For example, miR-155 increases the production of inflammatory cytokines and activates immune effector cells in the heart during infection, but switches to an anti-inflammatory and cardioprotective role during sepsis (110). Similarly, miR-21 levels correlate positively with the severity of myocarditis (111,112), although one study showed opposing result that injecting miR-21 to mice with VMC relieves disease severity (113).…”

“…In mice with EAM, miR-223-3p ameliorated inflammatory response by targeting pyrin domain-containing-3 (NLRP3) inflammasome which is a multiprotein complex and sensor in innate immune cells (140). miR-21, miR-146b, and miR-155 are consistently up-regulated in patients with acute VMC (141), and mice with myocarditis induced by CVB3 or T. cruzi (112). Consistent with this, intravenous injection of miR-21 and -146b antagonists decreased the expression levels of Th17 and RORγt, and attenuated cardiac inflammation and myocardial damage in a murine model of VMC (111).…”

Up-regulation of MicroRNAs-21 and -223 in a Sprague-Dawley Rat Model of Traumatic Spinal Cord Injury

“…After histopathologic examinations, total miR samples were extracted from the parenchyma of the SC. This is followed by the quantitative RT-PCR [27][28][29][30][31][32][33].…”