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Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways.

ABSTRACT: Chagas disease, the clinical presentation of T. cruzi infection, is a major human health concern. While the acute phase of Chagas disease is typically asymptomatic and self-resolving, chronically infected individuals suffer numerous sequelae later in life. Cardiomyopathies in particular are the most severe consequence of chronic Chagas disease and cannot be reversed solely by parasite load reduction. To prioritize new therapeutic targets, we unbiasedly interrogated the host signaling events in heart tissues isolated from a Chagas disease mouse model using quantitative, multiplexed proteomics. We defined the host response to infection at both the proteome and phospho-proteome levels. The proteome showed an increase in the immune response and a strong repression of several mitochondrial proteins. Complementing the proteome studies, the phospho-proteomic survey found an abundance of phospho-site alterations in plasma membrane and cytoskeletal proteins. Bioinformatic analysis of kinase activity provided substantial evidence for the activation of NDRG2 and JNK/p38 kinases during Chagas disease. A significant activation of DYRK2 and AMPKA2 and the inhibition of casein family kinases were also predicted. We concluded our analyses by linking the diseased heart proteome profile to known therapeutic interventions, uncovering a potential to target mitochondrial proteins, secreted immune effectors and core kinases for the treatment of chronic Chagas disease. Together, this study provides molecular insight into host proteome and phospho-proteome responses to T. cruzi infection in the heart for the first time, highlighting pathways that can be further validated for functional contributions to disease and suitability as drug targets.

SUBMITTER: Wozniak JM

PROVIDER: S-EPMC7279607 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways.

Wozniak Jacob M JM Silva Tatiana Araújo TA Thomas Diane D Siqueira-Neto Jair L JL McKerrow James H JH Gonzalez David J DJ Calvet Claudia M CM

PLoS neglected tropical diseases 20200520 5

Chagas disease, the clinical presentation of T. cruzi infection, is a major human health concern. While the acute phase of Chagas disease is typically asymptomatic and self-resolving, chronically infected individuals suffer numerous sequelae later in life. Cardiomyopathies in particular are the most severe consequence of chronic Chagas disease and cannot be reversed solely by parasite load reduction. To prioritize new therapeutic targets, we unbiasedly interrogated the host signaling events in h ...[more]

PMID: 32433643

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Project description: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-γ, 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.

Project description:Chagas cardiomyopathy is a chronic sequela of infection by the parasite, Trypanosoma cruzi. Advanced cardiomyopathy is associated with a high mortality rate, and clinical characteristics have been used to predict mortality risk. Though multiple biomarkers have been associated with Chagas cardiomyopathy, it is unknown how these are related to survival.This study aimed to identify biomarkers associated with mortality in individuals with severe Chagas cardiomyopathy in an urban Bolivian hospital.The population included individuals with and without T. cruzi infection recruited in an urban hospital in Santa Cruz, Bolivia. Baseline characteristics, electrocardiogram findings, medications, and serum cardiac biomarker levels (B-type natriuretic peptide [BNP], N-terminal pro-B-type natriuretic peptide [NT-proBNP], creatine kinase-myocardial band [CK-MB], troponin I, matrix metalloproteinase [MMP]-2, MMP-9, tissue inhibitor of metalloproteinases [TIMP] 1 and 2, transforming growth factor [TGF] beta 1 and 2) were ascertained. Echocardiograms were performed on those with cardiac symptoms or electrocardiogram abnormalities at baseline. Participants were contacted approximately 1 year after initial evaluation; deaths were reported by family members. Receiver-operating characteristic curves (ROC) were used to optimize cutoff values for each marker. For markers with area under the curve (AUC) >0.55, Cox proportional hazards models were performed to determine the hazards ratio (HR) and 95% confidence interval (CI) for the association of each marker with mortality.The median follow-up time was 14.1 months (interquartile range 12.5, 16.7). Of 254 individuals with complete cardiac data, 220 (87%) had follow-up data. Of 50 patients with severe Chagas cardiomyopathy at baseline, 20 (40%) had died. Higher baseline levels of BNP (HR: 3.1, 95% CI: 1.2 to 8.4), NT-proBNP (HR: 4.4, 95% CI: 1.8 to 11.0), CK-MB (HR: 3.3, 95% CI: 1.3 to 8.0), and MMP-2 (HR: 4.2, 95% CI: 1.5 to 11.8) were significantly associated with subsequent mortality.Severe Chagas cardiomyopathy is associated with high short-term mortality. BNP, NT-proBNP, CK-MB, and MMP-2 have added predictive value for mortality, even in the presence of decreased ejection fraction and other clinical signs of congestive heart failure.

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Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways.

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Molecular dissection of Chagas induced cardiomyopathy reveals central disease associated and druggable signaling pathways.

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