Chloroquine resistance and the physiology of the malaria parasite s digestive vacuole

疟疾是一种传染病，由一种单细胞寄生虫侵入其人类宿主的红细胞引起。每年，疟疾造成多达300万人死亡，其中大多数是5岁以下的儿童。这种寄生虫对目前可用的大多数（如果不是全部的话）抗疟疾药物产生了抗药性，而且没有疫苗。因此，迫切需要开发新的抗疟疾药物，并制定克服疟原虫耐药机制的策略。氯喹多年来一直是抗疟化疗的主要药物，在许多意义上，它是一种廉价、安全、有效的“特效药”。然而，对氯喹具有耐药性的寄生虫的出现和传播意味着，这种药物现在作为抗疟药基本上是无用的。氯喹通过作用于寄生虫的消化液泡来杀死（敏感的）寄生虫。消化液泡是寄生虫体内的酸性隔间，寄生虫在其中分解从宿主红细胞中摄取的蛋白质。这个隔室在寄生虫的生长和增殖中起着至关重要的作用。然而，我们对它的基本生理学知之甚少，我们也不了解抗氯喹寄生虫能够在暴露于氯喹的情况下存活的机制。这项工作的目的是为了进一步了解寄生虫消化液泡的生理机制，以及影响氯喹在这个隔间内积累的一些因素。前一部分工作很可能揭示新的抗疟疾药物靶点。这项工作的后一部分将增加我们对氯喹耐药机制的了解，从而为可能绕过这些机制的战略奠定基础，并使氯喹相关药物重新回到我们正在进行的和日益绝望的疟疾斗争的前线。

Malaria is an infectious disease, caused by a single-celled parasite which invades the red blood cells of its human host. Each year, malaria causes the death of up to 3 million people, mostly children under the age of 5 The parasite has become resistant to most, if not all, of the antimalarial drugs presently available, and there is no vaccine. There is therefore an urgent need to develop new antimalarial drugs, and-or to devise strategies for overcoming the parasite s drug resistance mechanisms. Chloroquine was, for many years, the mainstay of antimalarial chemotherapy and was, in many senses, a 'wonder-drug' cheap, safe and effective. However the emergence and spread of parasites that are resistant to chloroquine has meant that the drug is now largely useless as an antimalarial. Chloroquine kills (sensitive) parasite through an effect on the parasite s digestive vacuole an internal acidic compartment in which the parasite breaks down protein taken up from its host red blood cell. This compartment plays a crucial role in the growth and proliferation of the parasite. Yet we understand very little about its basic physiology, and nor do we understand the mechanism by which chloroquine-resistant parasites are able to survive exposure to the drug. The aim of the work proposed here is to gain an increased understanding of some of the mechanisms underlying the physiology of the parasite s digestive vacuole, as well as some of the factors influencing the accumulation of chloroquine within this compartment. The former part of the work may well reveal new antimalarial drug targets. The latter part of the work will increase our understanding of the mechanism of chloroquine resistance, thereby laying the groundwork for strategies by which these mechanisms might be circumvented and chloroquine-related drugs thereby restored to the front-line of our ongoing and increasingly desperate fight against malaria.