Mechanisms of Infection Chronicity and Pathogenesis in Gastrointestinal Chagas disease

恰加斯病是由原生动物寄生虫克氏锥虫引起的。恰加斯病是一种被忽视的热带疾病，影响着拉丁美洲数百万人。感染者终生携带这种寄生虫，但许多人从未经历过任何症状。其他人则会出现影响心脏和/或消化道的严重问题。人们进展为不同类型疾病的原因尚不清楚。在慢性感染期间，只有少量的寄生虫存在，它们位于细胞内、固体组织内。这使得检测寄生虫和调查它们在疾病过程中的作用变得困难。我们开发了一种技术，使这些实验变得容易得多。它是基于转基因的克氏锥虫，这种寄生虫已经被改造成表达一种发光酶。通过测量寄生虫发出的光的强度，我们可以在活着的小鼠体内和特定器官中跟踪和量化它们。我们已经将这个系统应用于研究查加斯心脏病的发展，并测试药物是否可以治愈小鼠的旋毛虫感染。在这个项目中，我们现在将应用这项技术来研究恰加斯病的消化形式。首先，我们将找出小鼠消化道的哪些部分受到克氏毛虫感染，并询问寄生虫或具有不同基因的小鼠是否与不同程度的疾病严重程度有关。接下来，我们将分析影响肠道肌肉和控制它们的神经系统部分的微观变化。我们还将调查小鼠的免疫系统对克氏锥虫的反应，并找出这些反应是否在疾病的发展中发挥作用。最后，我们将测试苯硝唑，一种可以治愈小鼠毛滴虫感染的药物，是否也可以防止消化病理的发展和进展。总之，这些研究将更好地了解克氏毛滴虫是如何引起慢性感染并导致影响胃肠道的症状性恰加斯病的。这将有助于加快开发治疗患者的新策略。

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi. Chagas is a neglected tropical disease that affects millions of people from Latin America. Infected people carry the parasite for life but many never experience any symptoms. Others develop serious problems affecting the heart and/or the digestive tract. The reasons why people progress to different types of disease is not well understood. During chronic infections, only small numbers of parasites are present and they are located inside cells, within solid tissue. This has made it difficult to detect parasites and investigate their contribution to the disease process. We developed a technique that makes these experiments much easier. It is based on transgenic T. cruzi parasites that have been engineered to express a light-emitting enzyme. By measuring the intensity of light emitted by the parasites we can track and quantify them inside live mice and in specific organs. We have already applied this system to study the development of Chagas heart disease and to test whether drugs can cure T. cruzi infections in mice. In this project we will now apply this technology to investigate the digestive form of Chagas disease. First we will find out which parts of the mouse's digestive tract are affected by T. cruzi infection and ask whether parasites or mice with different genetics are associated with different levels of disease severity. Next we will analyse the microscopic changes that affect the gut's muscles and the parts of the nervous system that control them. We will also investigate how the mouse's immune system responds to T. cruzi, and find out if these responses play a part in the development of disease. Finally, we will test whether benznidazole, a drug that can cure mice of T. cruzi infection, can also prevent the development and progression of digestive pathology. Together these studies will provide a much better understanding of how T. cruzi causes chronic infections and leads to symptomatic Chagas disease affecting the GI tract. This will help accelerate the development of novel strategies to treat patients.