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。

• 批准号: 10421179
• 负责人: Kathryn Marie Jones
• 金额: $ 78.35万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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/10421179
• 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; Complement component C4a; 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; Interferons; 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; 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; Vaccines; Work; acylcarnitine; base; 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; targeted treatment; treatment strategy; vector-borne

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.

慢性锥虫感染中心肌炎和进行性心脏纤维化的机制 抽象的： 由载体传播的细胞内原生动物寄生虫锥虫Cruzi感染引起的Chagas病， 全球约有650万人。克鲁齐（T. cruzi）的慢性感染导致持续的低级 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chagasic 心肌病（CCC）。 CCC患者的心脏炎症，纤维化和循环较高 与疾病严重程度相关的炎症和纤维化标记。抗寄生虫药苯甲酰唑失败 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，以识别目标 治疗干预措施。 T. Cruzi通过多种机制诱导宿主炎症和纤维化途径。 根据我们对这些机制的了解，我们开发了一种由T. Cruzi组成的免疫疗法 衍生的抗原TC24-C4和TLR4激动剂佐剂。我们以前表明免疫疗法 单独或与苯甲酰唑合并在疫苗连接的化学疗法策略中，调节宿主炎症 免疫反应并导致心肌炎和纤维化减少。此外，我们已经证明了类似于 肺，皮肤和肝纤维化的小鼠模型，用小分子TTI-101抑制STAT3激活 在CCC小鼠模型中，显着降低了心脏纤维化。这项工作导致了我们的中心假设，即 靶向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。在我们的初步数据的基础上，我们提出了三个 具体目的是评估这种联合治疗方案的功效：1）确定目标的影响 干预措施（免疫疗法，苯甲酰唑和TTI-101）调节寄生虫引起的炎症 免疫反应； 2）确定靶向干预措施对调节寄生虫诱导的纤维化的影响 回复; 3）确定靶向干预措施对调节寄生虫诱导的代谢的影响 回答。通过这些目标，我们将更好地定义CCC的发病机理，特别是相对 宿主炎症，纤维化和代谢失调对疾病进展的贡献。目标 恢复炎症，纤维化和代谢途径正常的干预措施，并保留心脏 健康，将帮助我们确定对CCC有助的关键宿主响应机制。另外，这些研究 将提供重要的概念证明，以制定针对的多模式治疗策略 CCC的寄生虫和潜在的组织病理，以保留心脏健康并最终改善临床 结果。