The importance of the mitochondrial ATP synthase to the survival of the malaria parasite

尽管进行了几十年的研究，但疟疾仍然是世界上最致命的疾病之一，有3亿至5亿新感染病例，100多万人死亡。属于疟原虫属的单细胞真核寄生虫是疟疾的病原体。这种寄生虫显示出一个相当复杂的生命周期，它开始于按蚊在被感染宿主的血液中摄取寄生虫。经过几个发育步骤后，疟原虫到达蚊子的唾液腺，并在下一次吸血时被注射到新的宿主体内。在哺乳动物宿主体内，寄生虫感染肝细胞并在肝细胞内发育而不引起任何临床症状。每一种寄生虫都会形成数千个所谓的分裂子，这些分裂子被释放到血液中。然后这些分裂子侵入红细胞，这标志着临床症状的开始。早期生化试验表明，在血液阶段，疟疾寄生虫几乎完全通过糖酵解来满足其ATP需求，在这一阶段不需要氧化磷酸化。然而，我们的初步数据表明，ATP合成酶是通过氧化磷酸化产生ATP的关键酶，在血液阶段表达。我们将应用反向遗传学来阐明这一点和其他关于疟原虫线粒体ATP合酶的矛盾数据。我们也将扩展我们的研究到疟疾蚊子和肝脏阶段。这项研究项目的结果可能揭示ATP合酶是一种有效的药物靶点，也是开发疟疾疫苗的起点。

Despite several decades of research, with 300 to 500 million new infections and over 1 million deaths, malaria is still one of the world most deadly diseases. Single-celled eukaryotic parasites belonging to the genus Plasmodium are the causative agent of malaria. This parasite shows a rather complex life cycle, which begins with the uptake of the parasite into an Anopheles mosquito during a blood meal on an infected host. After several developmental steps Plasmodium parasites reach the mosquitos salivary glands and are injected into a new host during the next blood meal. Inside the mammalian host the parasite infects liver cells and develops within them without causing any clinical symptoms. Every parasite formes several thousands of so called merozoites, which are released into the bloodstream. These merozoites then invade red blood cells, which marks the beginning of clinical symptoms. Early biochemical tests have shown that during the blood stage the malaria parasite covers its ATP requirements almost solely by glycolysis with oxidative phosphorylation not being needed at this stage. Our preliminary data however shows that the ATP synthase, the key enzyme for ATP production through oxidative phosphorylation, is expressed during the blood stage. We will apply reverse genetics to shed light on this and other contradictive data on the mitochondrial ATP synthase of Plasmodium. We will also expand our studies to the malaria mosquito- and liver stage. The results of this research project could reveal the ATP synthase as a valid drug target as well as the starting point for the development of a vaccine against malaria.