Interrogating host-parasite interactomes with multiscale proteomics

疟疾是一种由恶性疟原虫引起的急性疾病，每年直接导致数十万人死亡。当受感染的蚊子穿透皮肤时，恶性疟原虫就会进入人体血液。然后，这种寄生虫会穿透红细胞，并在其中安家。在这里，它可以躲避人类免疫系统，同时为它创造一个生存的地方。这一过程通常被称为重塑。这种寄生虫逃避人类免疫系统的非凡能力，使根除或设计新的治疗方法变得如此具有挑战性。尽管恶性疟原虫显然很重要，但它如何重塑红细胞的细节仍不清楚。我们已经知道，这种寄生虫使用红细胞自身的一些蛋白质来执行必要的功能，但对哪些蛋白质没有准确的理解。了解寄生虫使用了哪些蛋白质是很重要的，这样我们就可以设计药物来阻止它的踪迹。首先，这项研究将生成寄生虫与宿主人类细胞之间的相互作用图，同时寄生虫正在重塑红细胞以达到其目的。其次，关键的相互作用需要更详细地了解，我们将使用其他方法来观察人类蛋白质在被寄生虫使用时如何改变形状。这将让我们对它们的运作方式有重要的了解。最后，我们将开发一种新的方法，使我们能够检查这些相互作用在红细胞内是如何变化的。综合这些数据，我们将对重塑过程有一个新的理解。特别是，它将告诉药物化学家如何设计治疗疟疾寄生虫的新药。

Malaria is an acute disease caused by the parasite Plasmodium Falciparum, which is directly responsible for hundreds of thousands of deaths per year. Plasmodium Falciparum enters the human bloodstream when an infected mosquito penetrates the skin. The parasite then penetrates red blood cells and makes its home inside them. Here, it can hide from the human immune system whilst creating a place for it to survive. This process is often referred to as remodeling. The parasite's remarkable ability to evade the human immune system is what makes it so challenging to eradicate or design new therapeutics against it.Despite its clear importance the details of how Plasmodium Falciparum remodels the red blood cell is still unclear how it does this. We already know that the parasite uses some of the red blood cells' own proteins to carry out the necessary functions but do not have a precise understanding of which ones. It is important to understand which proteins the parasite is using so we can design drugs to stop it in its tracks.Firstly, this research will generate a "map" of interactions between the parasite and the host human cells whilst the parasite is remodeling the red blood cells for its purposes. Secondly, key interactions need to be understood in more detail and we will use other methods to see how human proteins change shape when they are used by the parasite. This will give us key insights into how they function. Finally, we will develop a new method that will allow us to examine how these interactions are changing inside the red blood cells. Together these data will provide us a new understanding of the remodeling process. In particular, it will inform medicinal chemists how to design new drugs against the malaria parasite.