Signal Transducer and Activator of Transcription-3 Modulation of Cardiac Pathology in Chronic Chagasic Cardiomyopathy

Abstract

Chronic Chagasic cardiomyopathy (CCC) is a severe clinical manifestation that develops in 30%–40% of individuals chronically infected with the protozoal parasite Trypanosoma cruzi and is thus an important public health problem. Parasite persistence during chronic infection drives pathologic changes in the heart, including myocardial inflammation and progressive fibrosis, that contribute to clinical disease. Clinical manifestations of CCC span a range of symptoms, including cardiac arrhythmias, thromboembolic disease, dilated cardiomyopathy, and heart failure. This study aimed to investigate the role of signal transducer and activator of transcription-3 (STAT3) in cardiac pathology in a mouse model of CCC. STAT3 is a known cellular mediator of collagen deposition and fibrosis. Mice were infected with T. cruzi and then treated daily from 70 to 91 days post infection (DPI) with TTI-101, a small molecule inhibitor of STAT3; benznidazole; a combination of benznidazole and TTI-101; or vehicle alone. Cardiac function was evaluated at the beginning and end of treatment by echocardiography. By the end of treatment, STAT3 inhibition with TTI-101 eliminated cardiac fibrosis and fibrosis biomarkers but increased cardiac inflammation; serum levels of interleukin-6 (IL-6), and IFN−γ; cardiac gene expression of STAT1 and nuclear factor-κB (NF-κB); and upregulation of IL-6 and Type I and Type II IFN responses. Concurrently, decreased heart function was measured by echocardiography and myocardial strain. These results indicate that STAT3 plays a critical role in the cardiac inflammatory–fibrotic axis during CCC.

Trypanosoma cruzi Dysregulates piRNAs Computationally Predicted to Target IL-6 Signaling Molecules During Early Infection of Primary Human Cardiac Fibroblasts

“…1B ). Other studies suggested that disruption of IL-6 expression and downstream targets during parasite infection play important roles in T. cruzi pathogenesis ( 5 6 7 47 ). These results suggest that these piRNAs may be important modulators of IL6 and SOCS3 gene expression during the early/acute phase of T. cruzi infection and pathogenesis.…”

“…Since the IL-6 pathway has been shown to be important in T. cruzi pathogenesis ( 6 47 ), we decided to evaluate the expression of those piRNAs in T. cruzi challenged PHCF because their differential expression could be context dependent ( 41 42 43 ). To evaluate the expression of IL6 , SOCS3 , and the piRNAs of interest that can target them, we challenged PHCF with T. cruzi trypomastigotes for various time points (0, 1, 3, and 6 h), and extracted total and small RNAs for our RT-qPCR assays.…”

“…Thus, there is a need to understand the molecular mechanisms of T. cruzi pathogenesis to facilitate identification of biomarkers and new therapeutic targets. The IL-6 signaling pathway has been suggested to play important roles in experimental and clinical T. cruzi pathogenesis ( 5 6 7 ). IL-6 is a cytokine with diverse roles in endothelial cell function, inflammation, and fibrogenesis ( 8 9 10 11 ).…”

“…High levels of IL-6 has been associated with disease severity in Chagas disease patients and murine model of T. cruzi infection ( 32 33 ). A recent study suggested that inhibition of STAT3 led to worsening of cardiac function in a murine model of T. cruzi infection through unknown mechanisms ( 6 ). We and others showed that T. cruzi upregulates the transcript and protein levels of IL-6 during early infection of cardiomyocytes and inflammatory cells ( 34 35 36 ).…”

C57BL/6 Mice Pretreated With Alpha-Tocopherol Show a Better Outcome of Trypanosoma cruzi Infection With Less Tissue Inflammation and Fibrosis

“…Also, vaccines are unavailable, and there are no alternative treatment options currently available. Therefore, strategies or potential drugs are highly desirable to diminish inflammation and fibrosis during the infection (18).…”