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 d… Show more
“…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.…”
Section: Resultsmentioning
confidence: 99%
“…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.…”
Section: Resultsmentioning
confidence: 99%
“…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 ).…”
Section: Introductionmentioning
confidence: 99%
“…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 ).…”
Trypanosoma cruzi
, the etiological agent of Chagas disease, is an intracellular protozoan parasite, which is now present in most industrialized countries. About 40% of
T. cruzi
infected individuals will develop severe, incurable cardiovascular, gastrointestinal, or neurological disorders. The molecular mechanisms by which
T. cruzi
induces cardiopathogenesis remain to be determined. Previous studies showed that increased IL-6 expression in
T. cruzi
patients was associated with disease severity. IL-6 signaling was suggested to induce pro-inflammatory and pro-fibrotic responses, however, the role of this pathway during early infection remains to be elucidated. We reported that
T. cruzi
can dysregulate the expression of host PIWI-interacting RNAs (piRNAs) during early infection. Here, we aim to evaluate the dysregulation of IL-6 signaling and the piRNAs computationally predicted to target IL-6 molecules during early
T. cruzi
infection of primary human cardiac fibroblasts (PHCF). Using in silico analysis, we predict that piR_004506, piR_001356, and piR_017716 target
IL6
and
SOCS3
genes, respectively. We validated the piRNAs and target gene expression in
T. cruzi
challenged PHCF. Secreted IL-6, soluble gp-130, and sIL-6R in condition media were measured using a cytokine array and western blot analysis was used to measure pathway activation. We created a network of piRNAs, target genes, and genes within one degree of biological interaction. Our analysis revealed an inverse relationship between piRNA expression and the target transcripts during early infection, denoting the IL-6 pathway targeting piRNAs can be developed as potential therapeutics to mitigate
T. cruzi
cardiomyopathies.
“…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.…”
Section: Resultsmentioning
confidence: 99%
“…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.…”
Section: Resultsmentioning
confidence: 99%
“…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 ).…”
Section: Introductionmentioning
confidence: 99%
“…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 ).…”
Trypanosoma cruzi
, the etiological agent of Chagas disease, is an intracellular protozoan parasite, which is now present in most industrialized countries. About 40% of
T. cruzi
infected individuals will develop severe, incurable cardiovascular, gastrointestinal, or neurological disorders. The molecular mechanisms by which
T. cruzi
induces cardiopathogenesis remain to be determined. Previous studies showed that increased IL-6 expression in
T. cruzi
patients was associated with disease severity. IL-6 signaling was suggested to induce pro-inflammatory and pro-fibrotic responses, however, the role of this pathway during early infection remains to be elucidated. We reported that
T. cruzi
can dysregulate the expression of host PIWI-interacting RNAs (piRNAs) during early infection. Here, we aim to evaluate the dysregulation of IL-6 signaling and the piRNAs computationally predicted to target IL-6 molecules during early
T. cruzi
infection of primary human cardiac fibroblasts (PHCF). Using in silico analysis, we predict that piR_004506, piR_001356, and piR_017716 target
IL6
and
SOCS3
genes, respectively. We validated the piRNAs and target gene expression in
T. cruzi
challenged PHCF. Secreted IL-6, soluble gp-130, and sIL-6R in condition media were measured using a cytokine array and western blot analysis was used to measure pathway activation. We created a network of piRNAs, target genes, and genes within one degree of biological interaction. Our analysis revealed an inverse relationship between piRNA expression and the target transcripts during early infection, denoting the IL-6 pathway targeting piRNAs can be developed as potential therapeutics to mitigate
T. cruzi
cardiomyopathies.
“…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).…”
Chagas disease is accompanied by a multisystem inflammatory disorder that follows Trypanosoma cruzi infection. Alpha-tocopherol has been described as an antioxidant and a potential adjuvant to enhance immune responses to vaccines. Therefore, we have evaluated the immune response to T. cruzi infection upon alpha-tocopherol pre-administration. The results show that administration of alpha-tocopherol before the infection results in lower parasitemia and lower mortality of C57BL/6 mice infected with the Tulahuen T. cruzi strain. Alpha-tocopherol administration in normal C57BL/6 mice resulted in higher levels of IFN-γ production by T and NK cells before and after the infection with T. cruzi. More importantly, previous administration of alpha-tocopherol increased the production of IL-10 by T and myeloid suppressor cells and the formation of effector memory T cells while decreasing the expression of PD-1 on T cells. These results suggest that alpha-tocopherol may limit the appearance of dysfunctional T cells during the acute and early chronic phases of T. cruzi infection, contributing to control infection. In addition, alpha-tocopherol could diminish tissue inflammation and fibrosis in late acute disease. These results strongly suggest that alpha-tocopherol may be a helpful agent to be considered in Chagas disease.
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