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造成了严重的代价，并消耗了可用于促进发展中国家增长的资源。目前还没有针对这种疾病的有效疫苗，化疗是减轻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，巴西每年记录有6000例。不幸的是，可用于治疗VL的药物有许多局限性，迫切需要新的药物。我们在这个合作项目中的目标是描述导致巴西VL的寄生虫chagasi利什曼原虫的关键生物学过程，从而确定影响疾病结果的因素。我们已经证明肽酶，消化蛋白质的酶，以及阻断肽酶功能的天然抑制剂，在寄生虫的传染性和致病性中是重要的。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体内的肽酶是否对疾病的发病机制起重要作用。为了做到这一点，我们将使用一种动物感染模型，使用L. chagasi寄生虫和老鼠。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纵，以发现编码蛋白在寄生虫的传染性和毒性中起什么作用，并确定它们是否可能被开发为新的治疗方法。其次，我们将研究利什曼原虫不同菌株的基因组变异。我们将对巴西Piaui州具有不同临床VL结果的患者分离的查加西L.寄生虫的基因组进行测序，并确定可能影响疾病表现的寄生虫基因。我们将整合动物模型和人类的寄生虫学和免疫学研究，总体而言，我们期望这项研究的结果能够大大提高对这些生物过程在利什曼原虫中的作用的理解，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.