Immunology and Immunopathology of visceral leishmaniasis

利什曼病是一种由白蛉叮咬引起的疾病，白蛉含有一种叫做利什曼原虫的小单细胞寄生虫。虽然有些人从不生病，但许多人会发展成局部皮肤溃疡或一种影响内脏的潜在致命疾病，称为内脏利什曼病（黑热病）。黑病?)。为什么不同的人会患上不同类型的疾病尚不清楚，但这可能与他们感染的利什曼原虫的类型和他们免疫系统的健康状况有关。每年有200万人感染利什曼病（在88个国家，包括欧洲的一些国家），内脏利什曼病每年造成6万多人死亡。由于寄生虫生活在组织深处（脾、肝、骨髓），在病人身上很难确切地看到它们是如何影响我们的免疫系统的，也很难找到改善免疫系统处理它们的方法。因此，我们需要利用疾病的实验模型来研究这些问题。尽管已经取得了很大的进展，但实验模型并不能提供全貌，在小鼠和人类对这些寄生虫的反应，或者在免疫系统对我们的器官造成多大程度的损害以对抗感染方面，可能存在重要的差异。我们希望开展一项综合研究计划，使我们能够同时研究人类和小鼠组织中的疾病过程。这种方法很重要，既可以看到小鼠的反应是否也发生在人类身上（从而支持在小鼠身上开发的药物/疫苗的临床研究），也可以反过来看看我们是否可以提高用于测试药物/疫苗的模型的预测性。我们将研究利什曼原虫是如何被肝脏中的白细胞（吞噬细胞）吞噬的，以及我们的基因表达是如何对感染做出反应的。我们将开发新的显微镜方法，使我们能够看到感染如何影响吞噬细胞功能及其协调炎症的能力。我们将使用在治疗期间和死后从人们身上采集的组织样本，观察他们的免疫系统对治疗的反应如何，或者了解导致他们死亡的问题所在。综合起来，这些研究将为人类疾病提供许多重要的新信息，并有助于减少和提高动物实验的质量。

Leishmaniasis is a disease caused when people are bitten by sandflies that contain a small single cell parasite, called Leishmania. Although some people never get sick, many develop local skin ulcers or a potentially fatal disease that affects the internal organs, called visceral leishmaniasis (kala azar or ?black sickness?). Why different people get different types of disease is not known, but it may relate to the type of Leishmania they are infected with and their health of their immune system. 2 million people get leishmaniasis every year (in 88 countries, including some in Europe) and visceral leishmaniasis is responsible for over 60,000 deaths annually. As the parasites live deep in the tissues (spleen, liver, bone marrow), it is difficult in sick people to see exactly how they are affecting our immune system and to find ways to improve how the immune system deals with them. Therefore, we need to use experimental models of the disease to study these questions. Although much progress has been made, experimental models cannot provide the whole picture and there may be important differences in how mice and people respond to these parasites, or in how much damage the immune system does to our organs trying to fight the infection. We wish to conduct an integrated research programme to let us study disease processes in human and mouse tissues side by side. This approach is important, both to see whether the responses in mice also occur in man (thus supporting clinical study of drugs/vaccines developed in mice) and conversely to see whether we can improve the predictive nature of models used for testing drugs/vaccines. We will be studying how Leishmania is eaten by white blood cells (phagocytes) in the liver, and how the expression of our genes changes in response to the infection. We will develop new microscopy approaches that allow us to see how infection affects phagocyte function and their ability to coordinate inflammation. We will use tissues samples taken from people during treatment and also at post mortem, to observe how well their immune systems have responded to treatment or to understand what went wrong that led to their death. In combination, these studies will provide much important new information on human disease, and help to reduce and improve the quality of animal experimentation.