Targeting purinergic signaling in Chagas disease

靶向恰加斯病中的嘌呤能信号传导

基本信息

批准号：
10662905
负责人：
Maria Pilar Aoki
金额：
$ 13.07万
依托单位：
NATIONAL RESEARCH COUNCIL OF ARGENTINA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662905
关键词：
Adenosine Argentina Benznidazole Biology Cardiac Cardiac Myocytes Cardiomyopathies Cell Density Cell Lineage Cell Separation Cells Cellular Immunity Chagas Disease Chagas Myocarditis Chronic Cicatrix Complication Consumption Country Development Disease Progression Drug Delivery Systems Drug Kinetics Environment Equilibrium Etiology Experimental Models Fostering Frequencies Gene Expression Growth Heart Heart failure Human Hypoxia Immune Immune response Immunity Immunohistochemistry Infection Inflammatory Response Intervention Investigation Ischemia Knowledge Latin America Lesion Leukocytes Link Macrophage Modeling Movement Mus Myeloid Cells Myocarditis Nucleosides Outcome Oxygen Parasites Particulate Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Population Preventive vaccine Public Health Purinoceptor Regulatory Pathway Reporting Role Signal Pathway Signal Transduction Sterility Stroke Sudden Death System T-Lymphocyte Testing Time Tissues Transplant Recipients Treatment Efficacy Trypanosoma cruzi Vaccine Therapy Validation affection chagasic cardiomyopathy chemotherapy clinically relevant extracellular immunopathology immunoregulation improved inflammatory milieu insight microbicide mouse model novel novel strategies pathogen pharmacologic response side effect

项目摘要

Project Summary Chagas disease, a major public health problem in Latin America, is caused by the infection with the protozoan parasite Trypanosoma (T.) cruzi and has been spread to non-endemic regions by migratory movements. Chagas cardiomyopathy represents the most severe complication of chronic Chagas disease in Argentina. This important illness has become a frequent cause of heart failure, cardio-embolic stroke, and sudden death in our and other endemic countries. There are still no effective prophylactic vaccines, and chemotherapy mainly relies on benznidazole, a 60-year-old drug linked to prolonged treatment and significant side effects. This parasite is an obligate intracellular pathogen that can infect any nucleated cell, but the clinically relevant niches are the cardiomyocytes since the parasite remains in the heart for several decades before the development of the cardiomyopathy. Therefore, one of the main challenges in understanding Chagas disease immunopathology is to find out why the parasite is not completely eliminated, being able to sustain a pathological inflammatory environment. After infection, the influx of immune cells consumes large amounts of oxygen, and ischemic cells rapidly respond to the hypoxic and inflammatory environment by releasing ATP to the extracellular milieu. This extracellular ATP (eATP) triggers microbicidal immune responses but is quickly hydrolyzed to the potent immunosuppressive metabolite adenosine, mainly via the concerted activity of CD39 and CD73 ectoenzymes. Increasing evidence suggests that the balance of purinergic signaling determines the immune response's outcome in different pathological scenarios. We hypothesize that the balance of purinergic responses to eATP and the nucleosides generated by CD39 and CD73 determines anti-T. cruzi immunity and triggers pathogenic mechanisms in Chagas disease. Hence, manipulating these signaling pathways could provide new approaches to limiting cardiac pathology. The central hypothesis will be tested by pursuing three specific aims: 1) Validate the participation of purinergic signaling in the cardiac response to T. cruzi infection in advanced human Chagas disease, 2) Determine the impact of CD39-CD73 ectoenzymes on the cellular immune response, and the progression of Chagas cardiomyopathy by employing experimental murine models, 3) Explore the benefits of pharmacological targeting of purinergic signaling in a mouse model of Chagas cardiomyopathy. These investigations will provide a comprehensive understanding of crucial mechanisms through which T. cruzi infection subverts immune response to sustain parasite persistence and a detailed insight into the biology of the cardiac response to infection. 1

项目摘要木马病是拉丁美洲的一个主要公共卫生问题，是由原生动物感染引起的寄生虫锥虫（T.）克鲁兹（T.查加斯心肌病代表了阿根廷慢性Chagas病的最严重并发症。这很重要疾病已成为心力衰竭，心脏栓塞性中风以及我们和其他猝死的经常原因流行国家。仍然没有有效的预防性疫苗，化学疗法主要依赖苯甲酸唑，一种60岁的药物，与长期治疗和显着副作用有关。这个寄生虫是可感染任何成核细胞的强制性细胞内病原体，但临床上相关的壁ches是心肌细胞由于寄生虫在心脏中保持了几十年心肌病。因此，理解查加斯疾病免疫病理学的主要挑战之一是找出为什么寄生虫不能完全消除，能够维持病理炎症环境。感染后，免疫细胞的流入消耗大量氧气和缺血细胞通过将ATP释放到细胞外环境中来快速应对低氧和炎症环境。这细胞外ATP（EATP）触发微生物免疫反应，但很快被水解为有效免疫抑制代谢产物腺苷，主要是通过CD39和CD73胞外酶的一致活性。越来越多的证据表明，嘌呤能信号的平衡决定了免疫反应的在不同的病理情况下的结果。我们假设嘌呤能反应对Eatp的平衡 CD39和CD73产生的核苷决定抗T。克鲁兹免疫和触发致病性夏加斯病的机制。因此，操纵这些信号通路可能会提供新的方法限制心脏病理。中央假设将通过追求三个具体目标来检验：1）验证嘌呤能信号传导参与心脏对克鲁兹感染的心脏反应疾病，2）确定CD39-CD73胞外酶对细胞免疫反应的影响，以及通过采用实验性鼠模型，Chagas心肌病的进展，3）探索的好处瓜加斯心肌病小鼠模型中嘌呤能信号传导的药理靶向。这些调查将提供对Cruzi T. Cruzi的关键机制的全面理解感染颠覆了维持寄生虫持久性的免疫反应，并详细洞察心脏对感染的反应。 1