Mechanisms of myocarditis and progressive cardiac fibrosis in chronic Trypanosoma cruzi infection.

慢性克氏锥虫感染心肌炎和进行性心脏纤维化的机制。

基本信息

批准号：
10594507
负责人：
Kathryn Marie Jones
金额：
$ 78.52万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-18 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594507
关键词：
Address Adjuvant Affect Agonist Antigens Antiparasitic Agents Benznidazole CD8-Positive T-Lymphocytes Cardiac Cardiac health Cells Chagas Disease Chronic Clinical Collagen Combined Modality Therapy Complex Data Deposition Development Disease Disease Progression Dose Echocardiography Electrocardiogram Emulsions Failure Fibrosis Goals Heart Heart failure Imaging Techniques Immune response Immunotherapy Infection Infiltration Inflammation Inflammatory Inflammatory Response Intervention Knowledge Link Liver Fibrosis Measures Metabolic Metabolic Pathway Metabolic dysfunction Mus Myocardial dysfunction Myocarditis Neuropathy Organ Preservation Outcome Parasites Pathogenesis Pathology Pathway interactions Patient-Focused Outcomes Patients Persons Phosphorylation Platelet-Derived Growth Factor Proteins Protozoa Pulmonary Fibrosis Recombinants STAT1 gene STAT3 gene Scheme Severities Severity of illness Signal Transduction Sudden Death TLR4 gene TNF gene Therapeutic Intervention Time Tissues Transforming Growth Factor beta Trypanosoma cruzi Tyrosine Phosphorylation Vaccines Vascular Diseases Work acylcarnitine chagasic cardiomyopathy chemotherapy chronic infection connective tissue growth factor coronary fibrosis cytokine efficacy evaluation heart function heart imaging heart metabolism heart preservation improved inflammatory marker intervention effect mouse model parasite invasion response skin fibrosis small molecule synergism targeted treatment treatment strategy vector-borne

项目摘要

Mechanisms of myocarditis and progressive cardiac fibrosis in chronic Trypanosoma cruzi infection Abstract: Chagas disease, caused by infection with the vector borne intracellular protozoal parasite Trypanosoma cruzi, affects approximately 6.5 million people worldwide. Chronic infection with T. cruzi results in persistent low grade myocarditis and progressive fibrosis, which results in significant cardiac dysfunction called Chronic Chagasic Cardiomyopathy (CCC). Patients with CCC have higher levels of cardiac inflammation, fibrosis, and circulating inflammatory and fibrotic markers that correlate with disease severity. The antiparasitic drug benznidazole fails to ameliorate the chronic inflammation and progressive fibrosis of CCC. Our long term goal is to define the mechanisms of host inflammation, fibrosis and metabolic dysregulation in CCC in an effort to identify targets for therapeutic interventions. T. cruzi induces host inflammatory and fibrotic pathways through multiple mechanisms. Based on our knowledge of these mechanisms, we developed an immunotherapy consisting of the T. cruzi derived antigen Tc24-C4 and a TLR4 agonist adjuvant. We previously showed that the immunotherapy, either alone or combined with benznidazole in a vaccine-linked chemotherapy strategy, modulates host inflammatory immune responses and results in reduced myocarditis and fibrosis. Additionally, we have shown that similar to mouse models of lung, skin and liver fibrosis, inhibiting STAT3 activation with the small molecule TTI-101 significantly reduces cardiac fibrosis in a mouse model of CCC. This work led to our central hypothesis that targeting host inflammatory and fibrotic pathways will synergize with anti-parasitic treatment to reduce cardiac inflammation and fibrosis and improve cardiac health in CCC. Building on our preliminary data, we propose three Specific Aims to evaluate efficacy of this combined treatment scheme: 1) Determine the effect of targeted interventions (immunotherapy, benznidazole and TTI-101) on modulating parasite-induced inflammatory immune responses; 2) Determine the effect of targeted interventions on modulating parasite-induced pro-fibrotic response; and 3) Determine the effect of targeted interventions on modulating parasite-induced metabolic responses. Through these aims, we will better define the pathogenesis of CCC, specifically the relative contribution of host inflammatory, fibrotic, and metabolic dysregulation to disease progression. Targeted interventions that restore the inflammatory, fibrotic and metabolic pathways to normal, and preserve cardiac health, will help us identify key host response mechanisms that contribute to CCC. Additionally, these studies will provide important proof of concept for developing multi-modal treatment strategies that target both the parasite and underlying tissue pathologies of CCC to preserve cardiac health and ultimately improve clinical outcomes.

慢性克氏锥虫感染心肌炎和进行性心脏纤维化的机制抽象的：恰加斯病，由载体传播的细胞内原生动物寄生虫克氏锥虫感染引起，影响全球约 650 万人。克氏锥虫的慢性感染导致持续低度感染心肌炎和进行性纤维化，导致严重的心脏功能障碍，称为慢性查加斯病心肌病（CCC）。 CCC 患者的心脏炎症、纤维化和循环能力较高与疾病严重程度相关的炎症和纤维化标志物。抗寄生虫药物苯并硝唑失败改善 CCC 的慢性炎症和进行性纤维化。我们的长期目标是定义 CCC 中宿主炎症、纤维化和代谢失调的机制，努力确定治疗靶点治疗干预。克氏锥虫通过多种机制诱导宿主炎症和纤维化途径。基于我们对这些机制的了解，我们开发了一种由克氏锥虫组成的免疫疗法衍生抗原 Tc24-C4 和 TLR4 激动剂佐剂。我们之前表明，免疫疗法要么单独或与疫苗相关化疗策略中的苯并硝唑联合使用，调节宿主炎症免疫反应并减少心肌炎和纤维化。此外，我们还证明了类似于肺、皮肤和肝纤维化小鼠模型，用小分子 TTI-101 抑制 STAT3 激活显着减少 CCC 小鼠模型的心脏纤维化。这项工作得出了我们的中心假设：针对宿主炎症和纤维化途径将与抗寄生虫治疗协同作用，以减少心脏炎症和纤维化并改善 CCC 的心脏健康。根据我们的初步数据，我们提出了三个建议评估该联合治疗方案疗效的具体目的： 1) 确定靶向治疗的效果调节寄生虫引起的炎症的干预措施（免疫疗法、苯硝唑和 TTI-101）免疫反应； 2) 确定针对性干预措施对调节寄生虫诱导的促纤维化的效果回复; 3) 确定有针对性的干预措施对调节寄生虫诱导的代谢的效果回应。通过这些目标，我们将更好地确定 CCC 的发病机制，特别是相关的宿主炎症、纤维化和代谢失调对疾病进展的贡献。有针对性使炎症、纤维化和代谢途径恢复正常并保护心脏的干预措施健康，将帮助我们确定有助于 CCC 的关键宿主反应机制。此外，这些研究将为制定针对以下疾病的多模式治疗策略提供重要的概念证明： CCC 的寄生虫和潜在组织病理学，以保护心脏健康并最终改善临床结果。