Targeting purinergic signaling in Chagas disease

项目摘要 南美锥虫病是拉丁美洲的一个主要公共卫生问题， 寄生虫锥虫（T.）cruzi，并已通过移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。这一重要 疾病已经成为我们和其他人心力衰竭、心源性栓塞性中风和猝死的常见原因 流行国家。目前还没有有效的预防性疫苗，化疗主要依靠 苯并咪唑，一种有60年历史的药物，与长期治疗和显著的副作用有关。这种寄生虫是 专性细胞内病原体，可以感染任何有核细胞，但临床相关的小生境是 心肌细胞，因为寄生虫在心肌细胞发育之前会在心脏中停留几十年 心肌病因此，理解恰加斯病免疫病理学的主要挑战之一是 找出为什么寄生虫没有完全消除，能够维持病理性炎症， 环境感染后，免疫细胞的涌入消耗了大量的氧气， 通过向细胞外环境释放ATP快速响应缺氧和炎症环境。这 细胞外ATP（eATP）触发杀微生物免疫反应，但很快被水解为有效的 免疫抑制代谢物腺苷，主要通过协同活性的CD39和CD73胞外酶。 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。我们推测eATP的嘌呤能反应平衡 由CD39和CD73产生的核苷决定抗T细胞。cruzi免疫和触发致病 恰加斯病的发病机制因此，操纵这些信号通路可以提供新的方法， 限制心脏病理学。中心假设将通过追求三个具体目标来检验：1） 嘌呤能信号通路参与T.晚期人类南美锥虫的克氏感染 2）确定CD39-CD73胞外酶对细胞免疫应答的影响，以及 通过采用实验小鼠模型研究查加斯心肌病的进展，3）探索 在查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 调查将提供一个全面的了解的关键机制，通过T。cruzi 感染破坏免疫反应，以维持寄生虫的持久性，并详细了解 心脏对感染的反应 1

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