Leishmania virulence factors and host peptidases associated with visceral leishmaniasis

利什曼病是一种严重的人类疾病，也是世界上最被忽视的疾病之一，主要影响发展中国家的穷人。3.5亿人面临感染这种疾病的风险，它在健康和经济方面都付出了沉重的代价，并消耗了本可用于促进发展中国家增长的资源。目前还没有有效的疫苗来对抗这种疾病，化疗是减少利什曼病负担的主要手段。内脏利什曼病（VL）是最严重的利什曼病，巴西每年有6,000例记录。不幸的是，可用于治疗VL的药物具有许多局限性，并且迫切需要新的药物。在这个合作项目中，我们的目标是研究导致巴西VL的寄生虫恰加斯利什曼原虫的关键生物过程，从而确定影响疾病结果的因素。我们已经表明，肽酶，消化蛋白质的酶，和天然抑制剂，阻止肽酶的功能，是重要的寄生虫的感染性和致病性。我们的工作将集中在寄生虫生物学及其与宿主相互作用的3个关键领域。首先，我们将测试哺乳动物宿主中的肽酶是否对疾病的发病机制很重要。为了做到这一点，我们将使用感染的动物模型，使用L。恰加斯寄生虫和小鼠。一个关键的方法将是对重要的利什曼原虫基因进行遗传操作，以找出编码的蛋白质在寄生虫的感染性和毒力中发挥的作用，并确定它们是否可以作为新的治疗方法加以利用。其次，我们将研究不同利什曼原虫株的基因组变异。我们将对L.在巴西皮奥伊州的患者中分离出具有不同临床VL结果的恰加斯寄生虫，并鉴定可能影响疾病表现的寄生虫基因。我们将在动物模型和人类中整合寄生虫学和免疫学研究，总体而言，我们预计这项研究的结果将大大提高对利什曼原虫这些生物过程的作用的理解，以及这些过程本身的分子机制-这将与生物学的许多领域相关。

Leishmaniasis is a severe disease of humans and one of the world's most neglected diseases, primarily affecting the poor in developing countries. 350 million people are at risk of contracting the disease and it has severe costs in both health and economic terms and drains resources that could be used to promote growth of developing nations. There is no effective vaccine against the disease and chemotherapy is the prime means for reducing the leishmaniasis burden. Visceral Leishmaniasis (VL) is the most severe form of leishmaniasis with 6,000 cases recorded in Brazil each year. Unfortunately the drugs available to treat VL have many limitations and new drugs are desperately needed. Our aim in this collaborative project is to characterise key biological processes of Leishmania chagasi, the parasite that causes VL in Brazil, and so identify factors that influence the outcome of disease. We have shown that peptidases, enzymes that digest proteins, and natural inhibitors that block peptidase function, are important in the infectivity and pathogenicity of the parasite. Our work will concentrate on 3 key areas of the biology of the parasite and its interaction with the host. Firstly, we will test if peptidases in the mammalian host are important for the pathogenesis of the disease. To do this we will use an animal model of infection using the L. chagasi parasite and mice. A key approach will be to genetically manipulate important Leishmania genes to find out what role the encoded proteins play in the parasite's infectivity and virulence and to determine whether they might be exploited as novel therapeutics. Secondly, we shall investigate the genome variation that occurs in different strains of Leishmania. We will sequence the genomes of L. chagasi parasites isolated from patients in the State of Piaui in Brazil with different clinical VL outcome and identify parasite genes that might influence the presentation of disease. We will integrate parasitological and immunological studies in animal models and humans and overall, we expect the outcome from this study to be a greatly improved understanding on the roles of these biological processes in Leishmania, and the molecular mechanisms of the processes themselves - which will be relevant to many areas of biology.