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

线粒体 ATP 合酶对疟原虫生存的重要性

• 批准号: 195530552
• 负责人: Dr. Angelika Sturm
• 金额: --
• 依托单位: School of BioSciences
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/195530552?language=en
• 关键词: importance; mitochondrial; ATP; synthase; survival

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.

尽管经过几十年的研究，疟疾仍是世界上最致命的疾病之一，新增感染3亿至5亿人，死亡100多万人。属于疟原虫属的单细胞真核寄生虫是疟疾的病原体。这种寄生虫显示了一个相当复杂的生命周期，从寄生虫在受感染宿主的血液进食过程中进入按蚊开始。经过几个发育步骤后，疟原虫到达蚊子的唾液腺，并在下一餐血液中被注射到新的宿主中。在哺乳动物体内，寄生虫感染肝细胞并在其中生长，而不会引起任何临床症状。每种寄生虫形成数千个所谓的裂殖子，这些裂殖子被释放到血液中。然后这些裂殖子侵入红细胞，这标志着临床症状的开始。早期的生化测试表明，在血液阶段，疟疾寄生虫几乎完全通过糖酵解来满足其对ATP的需求，而在这个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个和其他关于疟原虫线粒体ATP合成酶的相互矛盾的数据。我们还将把我们的研究扩展到疟疾、蚊子和肝脏阶段。这一研究项目的结果可能揭示ATP合成酶作为有效的药物靶点以及开发疟疾疫苗的起点。

项目成果

Mitochondrial ATP synthase is dispensable in blood-stage Plasmodium berghei rodent malaria but essential in the mosquito phase

• DOI: 10.1073/pnas.1423959112
• 发表时间: 2015-08-18
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Sturm, Angelika;Mollard, Vanessa;McFadden, Geoffrey I.
• 通讯作者: McFadden, Geoffrey I.