The pH of the malaria parasite's digestive vacuole and its role in antimalarial drug resistance

疟疾是一种传染病，估计每年感染3亿至5亿人，造成150万至270万人死亡。导致这种疾病的微小寄生虫对目前可用的大多数抗疟疾药物越来越具有耐药性。然而，人们对它的作用机制知之甚少。疟疾寄生虫侵入受害者的红细胞。一旦进入细胞，它就开始消耗细胞内的内容物，将它们吞下，并将它们存放在一个叫做消化液泡的酸性小隔间中。目前使用的许多抗疟疾药物以这个隔室为目标，并干扰其内部进行的过程。有证据表明，抗疟药物耐药性的产生是由于这一隔室发生变化的结果，尽管这些变化是什么以及它们是如何发生的仍然是一个谜。这项工作的重点是控制寄生虫消化液泡酸度的机制。我们有初步证据表明，表现出不同水平抗疟药耐药性的寄生虫在其液泡中具有不同水平的酸度，这可能是由于酸从这个隔室泄漏的速度不同。这项工作的目的是获得对寄生虫的消化液泡酸度的调节机制的详细了解，并获得一些关于这些机制是否以及如何在耐药和药敏寄生虫之间有所不同的见解。通过这样做，从长远来看，这项工作可能会为开发新药提供基础，以对抗这种致命且威胁日益严重的疾病。

Malaria is an infectious disease that infects an estimated 300-500 million people and kills an estimated 1.5-2.7 million people annually. The microscopic parasite responsible for the disease is becoming increasingly resistant to most of the antimalarial drugs presently available. However the mechanisms by which it does so are very poorly understood. The malaria parasite invades the red blood cells of its victim. Once itside, it sets about consuming the contents of the cell, ingesting them and depositing them in a small acidic compartment called the digestive vacuole. Many of the antimalarial drugs presently in use target this compartment and interfere with the processes going on inside it. There is evidence that resistance to antimalarial drugs arises as a result of changes in this compartment, though what these changes are, and how they occur remains a mystery. This work focuses on the mechanisms involved in controlling the acidity of the parasite's digestive vacuole. We have preliminary evidence that parasites showing different levels of antimalarial drug resistance have different levels of acidity in their vacuoles, and that this may be due to differences in the rate at which acid leaks from this compartment. The aim of this work is to obtain a detailed understanding on the mechanisms by which the acidity of the parasite's digestive vacuole is regulated and to gain some insight into whether and how these mechanisms might differ between drug-resistant and drug-sensitive parasites. By so doing, this work might be expected, in the long term, to provide a basis for the devolpment of new drugs with which to combat this deadly and increasingly threatening disease.