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)人类和动物的一种严重疾病，在卫生和经济方面都有严重的代价，并耗尽了本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。不幸的是，现有的药物有许多局限性，迫切需要新药。我们在这项工作计划中的目标是描述利什曼原虫的关键生物学过程，从而识别和验证潜在的药物靶标。我们已经证明了肽酶，一种消化蛋白质的酶，在利什曼原虫的发展中发挥着核心作用，在寄生虫的传染性和致病性中起着重要的作用。我们的工作将集中在寄生虫生物学的三个关键领域。首先，关于自噬(自相残杀)过程引起的细胞形状的变化，自噬导致传染性寄生虫的发展，并允许寄生虫生活在哺乳动物宿主内。我们现在的目标是阐明利什曼原虫自噬在不同刺激下的关键作用和分子机制，如饥饿和压力。我们将确定自噬对于利什曼原虫(一种生活在人类中的寄生虫形式)无鞭毛体繁殖的重要性，以及药物干预是否能有效地针对它。我们还将调查利什曼原虫是否将调节宿主细胞的自噬作为一种生存策略。其次，关于寄生虫的关键作用？S体内与哺乳动物宿主相互作用的膜结构，以及使寄生虫毒力的因子是如何从细胞中释放出来的。第三，我们将研究寄生虫特异性多肽酶的功能，它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对重要的利什曼原虫基因进行基因操作，以找出编码蛋白在这种寄生虫中扮演什么角色？S的传染性和毒力。这项研究的一个结果将是极大地提高对这些生物过程在利什曼病中的作用的理解，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。另一个预期的结果将是了解哪些肽酶是有效的药物靶标，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先导。

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.