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，在健康和经济方面都造成严重损失，并消耗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，迫切需要新的药物。我们在这项工作规划中的目标是描述利什曼原虫（引起利什曼病的寄生虫）的关键生物学过程，从而确定和验证潜在的药物靶点。我们已经证明肽酶，消化蛋白质的酶，在利什曼原虫的发展中起着核心作用，在寄生虫的传染性和致病性中很重要。我们的工作将集中在寄生虫生物学的三个关键领域。首先，自噬（自食）过程介导的细胞形状变化，导致感染性寄生虫的发展，并使寄生虫能够在哺乳动物宿主体内生存。我们现在的目的是阐明利什曼原虫在饥饿和应激等不同刺激下自噬的关键作用和分子机制。我们将确定自噬对利什曼原虫（生活在人类体内的寄生虫形式）无尾线虫繁殖的重要性，以及是否可以通过药物干预有效地靶向它。我们还将研究利什曼原虫是否调节宿主细胞的自噬作为一种生存策略。第二，关于寄生虫的关键作用？S与哺乳动物宿主相互作用的内部膜结构，以及使寄生虫具有毒性的因素如何从细胞中释放。第三，我们将研究寄生虫特异性肽酶metacaspase的功能，该酶对寄生虫的生长至关重要，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，以找出编码蛋白在寄生虫中发挥的作用。S传染性和毒力。这项研究的一个结果将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有关。另一个预期的结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.