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

项目概要恰加斯病是拉丁美洲的一个主要公共卫生问题，是由原虫感染引起的寄生虫克氏锥虫 (T.) 已通过迁徙运动传播到非流行地区。恰加斯心肌病是阿根廷慢性恰加斯病最严重的并发症。这个重要的疾病已成为我们和其他国家心力衰竭、心源性中风和猝死的常见原因流行国家。目前尚无有效的预防疫苗，化疗主要依靠苯并硝唑是一种已有 60 年历史的药物，与长期治疗和严重副作用有关。这种寄生虫是一种可以感染任何有核细胞的专性细胞内病原体，但临床相关的生态位是心肌细胞，因为寄生虫在心脏发育之前已在心脏中保留了数十年心肌病。因此，了解恰加斯病免疫病理学的主要挑战之一是找出寄生虫没有被完全消灭的原因，能够维持病理性炎症环境。感染后，免疫细胞大量涌入，消耗大量氧气，细胞缺血通过向细胞外环境释放 ATP 来快速响应缺氧和炎症环境。这细胞外 ATP (eATP) 会引发杀微生物免疫反应，但很快会被水解为有效的免疫抑制代谢物腺苷，主要通过 CD39 和 CD73 胞外酶的协同活性。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不同病理情况下的结果。我们假设 eATP 的嘌呤能反应的平衡 CD39和CD73产生的核苷决定抗T细胞。克鲁兹免疫并触发致病性查加斯病的机制。因此，操纵这些信号通路可以提供新的方法限制心脏病理学。将通过追求三个具体目标来检验中心假设：1）验证嘌呤能信号参与晚期人类恰加斯人克氏锥虫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，以及通过使用实验性小鼠模型来研究恰加斯心肌病的进展，3) 探索恰加斯心肌病小鼠模型中嘌呤能信号传导的药理学靶向。这些调查将提供对克氏锥虫赖以生存的关键机制的全面了解。感染破坏免疫反应以维持寄生虫的持久性以及对寄生虫生物学的详细了解心脏对感染的反应。 1