Analysing the roles of peptidases in Leishmania infectivity and pathogenicity

利什曼病是热带和亚热带（包括南欧）人类和动物的严重疾病，在健康和经济方面都有严重的代价，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。不幸的是，现有的药物有许多局限性，迫切需要新的药物。我们在这项工作计划中的目标是研究导致利什曼病的寄生虫利什曼原虫的关键生物过程，从而确定和验证潜在的药物靶点。我们已经表明，肽酶，消化蛋白质的酶，在利什曼原虫的发展中发挥核心作用，并在寄生虫的感染性和致病性中发挥重要作用。我们的工作将集中在寄生虫生物学的3个关键领域。首先，在细胞形状的变化介导的过程称为自噬（自食），这导致感染性寄生虫的发展，并允许寄生虫生活在哺乳动物宿主。本研究旨在阐明利什曼原虫自噬在饥饿和应激等不同刺激下的重要作用及其分子机制。我们将确定自噬对于利什曼原虫（生活在人类中的寄生虫形式）无鞭毛体增殖的重要性，以及它是否可以通过药物干预有效地靶向。我们还将研究利什曼原虫是否调节其宿主细胞中的自噬作为一种生存策略。第二，关于寄生虫的关键作用？寄生虫与哺乳动物宿主相互作用的内部膜结构，以及使寄生虫毒性的因子如何从细胞中释放。第三，我们将研究寄生虫特异性肽酶的功能，metacaspase，这是寄生虫生长所必需的，但其功能尚不清楚。一个关键的方法将是遗传操纵重要的利什曼原虫基因，以找出编码的蛋白质在寄生虫中发挥什么作用？的感染性和毒力。这项研究的一个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。另一个预期的成果将是了解哪些肽酶是有效的药物靶点，这些信息将通过合作发现肽酶抑制剂来利用，这应该是新药开发的领先者。

Leishmaniasis is a severe disease of humans and animals in the tropics and sub-tropics (including Southern Europe) and 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. Unfortunately the drugs available have many limitations and new drugs are desperately needed. Our aim in this programme of work is to characterise key biological processes of Leishmania, the parasite that causes leishmaniasis, and so identify and validate potential drug targets. We have shown that peptidases, enzymes that digest proteins, play central roles in the development of Leishmania and are important in the infectivity and pathogenicity of the parasite. Our work will concentrate on 3 key areas of the biology of the parasite. Firstly, on the changes in cell shape mediated by a process called autophagy (self-cannibalism), which leads to the development of infectious parasites and allows the parasite to live within a mammalian host. We now aim to elucidate the key roles and molecular mechanism of autophagy in Leishmania under different stimuli, such as starvation and stress. We will determine the importance of autophagy for the multiplication of amastigotes of Leishmania (the parasite form that lives in humans) and so whether it can be effectively targeted by drug intervention. We will also investigate whether Leishmania modulates autophagy in its host cell as a survival strategy. Secondly, on the crucial role of the parasite?s internal membranous structures for interactions with the mammalian host, and how factors that make the parasite virulent are released from the cell. Thirdly, we will investigate the function of a parasite-specific peptidase, metacaspase, which is essential for growth of the parasite but the function of which is unclear. 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. One outcome from this study will be 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. Another expected outcome will be knowledge on which peptidases are valid drug targets and this information will be exploited by collaborating to discover inhibitors of peptidases, which should be leads in the development of new drugs.