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TREATMENT WITH SUBOPTIMAL DOSE OF BENZNIDAZOLE MITIGATES IMMUNE RESPONSE MOLECULAR PATHWAYS IN MICE WITH CHRONIC CHAGAS CARDIOMYOPATHY
Doença de Chagas
Cardiomiopatia
Resposta imune
Matriz TaqMan
Benznidazol
Pentoxifilina
Trypanosoma cruzi
Cardiomyopathy
Immune response
TaqMan array
Benznidazole
Pentoxifylline
Author
Affilliation
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Plataforma PCR em tempo real RPT09A. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Department of Biological Sciences, Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Department of Biological Sciences, Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, USA.
Department of Biological Sciences, Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Plataforma PCR em tempo real RPT09A. Rio de Janeiro, RJ, Brasil.
Department of Biological Sciences, Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Department of Biological Sciences, Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, USA.
Department of Biological Sciences, Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doenças Endêmicas. Plataforma PCR em tempo real RPT09A. Rio de Janeiro, RJ, Brasil.
Abstract
Chronic Chagas cardiomyopathy (CCC) is the most frequent and severe form of Chagas
disease, a neglected tropical illness caused by the protozoan Trypanosoma cruzi, and the
main cause of morbimortality from cardiovascular problems in endemic areas. Although
efforts have been made to understand the signaling pathways and molecular mechanisms
underlying CCC, the immunological signaling pathways regulated by the etiological
treatment with benznidazole (Bz) has not been reported. In experimental CCC, Bz
combined with the hemorheological and immunoregulatory agent pentoxifylline (PTX)
has beneficial effects on CCC. To explore the molecular mechanisms of Bz or Bz+PTX
therapeutic strategies, C57BL/6 mice chronically infected with the T. cruzi Colombian
strain (discrete typing unit TcI) and showing electrocardiographic abnormalities were
submitted to suboptimal dose of Bz or Bz+PTX from 120 to 150 days postinfection.
Electrocardiographic alterations, such as prolonged corrected QT interval and heart
parasite load, were beneficially impacted by Bz and Bz+PTX. RT-qPCR TaqMan array
was used to evaluate the expression of 92 genes related to the immune response in RNA
extracted from heart tissues. In comparison with non-infected mice, 30 genes were
upregulated, and 31 were downregulated in infected mice. Particularly, infection
upregulated the cytokines IFN-g, IL-12b, and IL-2 (126-, 44-, and 18-fold change,
respectively) and the T-cell chemoattractants CCL3 and CCL5 (23- and 16-fold
change, respectively). Bz therapy restored the expression of genes related to
inflammatory response, cellular development, growth, and proliferation, and tissue
development pathways, most probably linked to the cardiac remodeling processes
inherent to CCC, thus mitigating the Th1-driven response found in vehicle-treated
infected mice. The combined Bz+PTX therapy revealed pathways related to the
modulation of cell death and survival, and organismal survival, supporting that this strategy may mitigate the progression of CCC. Altogether, our results contribute to the
better understanding of the molecular mechanisms of the immune response in the heart
tissue in chronic Chagas disease and reinforce that parasite persistence and dysregulated
immune response underpin CCC severity. Therefore, Bz and Bz+PTX chemotherapies
emerge as tools to interfere in these pathways aiming to improve CCC prognosis.
Keywords in Portuguese
Trypanosoma cruziDoença de Chagas
Cardiomiopatia
Resposta imune
Matriz TaqMan
Benznidazol
Pentoxifilina
Keywords
Chagas diseaseTrypanosoma cruzi
Cardiomyopathy
Immune response
TaqMan array
Benznidazole
Pentoxifylline
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