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: 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
• 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

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.

慢性克氏锥虫感染引起心肌炎和进行性心脏纤维化的机制