Structural changes to host and parasite during malarial egress from the human red blood cell

疟疾影响着世界上大约一半人口的生活，是5岁以下儿童的最大单一病原体杀手。目前还没有有效的疫苗，对许多现有抗疟疾药物的抗药性正在蔓延。迫切需要找到抗击这种疾病的新方法。疟疾寄生虫在红细胞内感染和生长，在一个被膜包裹的寄生虫空泡中分裂。最终，在一个被称为出口的快速、高度调控的过程中，寄生虫的表面被广泛修改，空泡和宿主细胞膜破裂，释放出称为裂殖子的成熟形式，这些成熟形式立即入侵新细胞。裂殖子表面是如何被修饰以准备释放和入侵的，以及最终如何发生膜破裂，目前尚不清楚。这项研究项目有两个相互关联的目标。首先，我们希望了解细胞内寄生虫破坏其结合膜稳定和破裂的分子机制。已知一种名为蛋白酶的特殊寄生虫酶在其中起着关键作用。同样的蛋白酶也会在释放前戏剧性地改变寄生虫表面本身，使其能够入侵新的红细胞，因此我们项目的第二个目标是探索这些表面蛋白修饰的性质、重要性和功能。为了做到这一点，我们将应用强大的新方法来研究分离的寄生虫表面分子的三维形状和结构，以及被寄生虫感染的细胞的三维形状和结构，这些细胞被快速冷冻，以将它们保存在接近生命的状态。通过将分子和膜的结构变化与功能变化联系起来，我们的发现将提高我们对寄生虫生命周期中这些关键步骤的理解，并应有助于揭示抗击这种毁灭性疾病的新方法。

Malaria impacts on the lives of about half of the world?s population and is the biggest single pathogen killer of children below the age of 5. There is no effective vaccine, and resistance to many available antimalarial drugs is spreading. There is an urgent need to find new ways of combating the disease. The malaria parasite infects and grows inside red blood cells, dividing within a membrane-bound parasitophorous vacuole. Eventually, in a rapid, highly regulated process called egress, the parasite surface is extensively modified and the vacuole and host cell membranes rupture, releasing mature forms called merozoites which immediately invade new cells. Exactly how the merozoite surface is modified to prepare it for release and invasion, and how eventual membrane rupture occurs, is unknown. This research project has two related aims. First, we wish to understand the molecular mechanisms by which the intracellular parasite destabilises and ruptures its bounding membranes. A particular parasite enzyme called a protease is known to play a key role in this. The same protease also dramatically alters the parasite surface itself just before release, to enable it to invade new red blood cells, and so the second aim of our project is to explore the nature, importance and function of these surface protein modifications. To do this, we will apply powerful new methods for studying the three-dimensional shape and structure of isolated parasite surface molecules, and of parasite-infected cells that have been rapidly frozen to preserve them in a close to living state. By linking structural changes in molecules and membranes to functional changes, our findings will improve our understanding of these critical steps in the parasite life cycle and should shed light on new ways to fight this devastating disease.