How does the trypanosome haptoglobin-hemoglobin receptor interact with nutrients and immunity molecules? Receptor structure to cellular mechanism.

锥虫是一种单细胞寄生虫，在撒哈拉以南非洲引起重大疾病。它们感染人类，导致非洲昏睡病。它们还感染包括牛在内的各种家畜，导致疾病，降低食物生产能力。锥虫在人类或动物宿主的血液中生活和分裂。为了在这种环境中生存，它们有一个高度适应的细胞表面。这使它们能够从血液中摄取营养分子，在生长和分裂过程中，它们可以用作能源或建筑材料。然而，这也将他们置于危险之中。如果它们被抗体识别，它们就可以被人体的免疫防御系统检测到并摧毁。人体还含有几种被称为胰溶因子的蛋白质复合体。如果被带入寄生虫体内，这些病毒会导致锥虫破裂和死亡。可以感染人类的锥虫物种已经找到了避免摄取锥虫溶解因子或阻止导致裂解的过程的方法。锥虫如何从血液中吸收营养分子并避免被抗体识别？它们被一种名为VSG的蛋白质所覆盖。这一涂层是动态的，VSG分子与附着的抗体一起被吸收到细胞中。抗体被降解，血管紧张素转换酶回到表面。这种寄生虫能够表达大量不同的VSG分子，它们可以切换使用哪种VSG来躲避免疫系统的检测。被用来摄取营养分子的受体蛋白必须在VSG层的背景下结合它们的货物，同时避免被免疫系统识别。在这个建议中，我们将使用各种不同的实验工具来研究这些受体之一-结合珠蛋白-血红蛋白受体(HpHbR)。这种受体处于寄生虫冲突的核心。它参与HPHb进入锥体细胞的摄取，寄生虫从锥体细胞获得Hem分子，使其能够建立自己的细胞结构。但它也是摄取胰酶因子，导致寄生虫死亡的主要途径。我们将使用结构生物学方法，详细了解受体如何识别其不同的货物，包括HPHb和胰酶因子。我们将把这一点与细胞生物学结合起来，使我们能够了解在寄生虫表面的背景下，配体摄取是如何发生的。这将是第一项将结构和细胞实验相结合的研究，以深入了解锥虫受体，揭示锥虫表面是如何适应的，以允许营养吸收，同时避免身体破坏。它还将展示毒素分子的摄取途径是如何发挥作用的。这是一条目前由天然胰酶因子使用的路线，有可能被颠覆，使药物和毒素分子能够专门针对这种致命的寄生虫。

Trypanosomes are single celled parasites that cause significant disease in Sub Saharan Africa. They infect humans, causing African sleeping sickness. They also infect a variety of domestic animals, including cattle, leading to disease that reduces food production capability.Trypanosomes live and divide in the blood of their human or animal host. To survive in this environment they have a highly adapted cell surface. This allows them to take up nutrient molecules from the blood, which they can use as sources of energy or building materials as they grow and divide. However, it also puts them in peril. If they are recognised by antibodies, they can be detected and destroyed by the body's immune defences.The human body also contains several protein complexes called trypanolytic factors. If taken up into the parasite, these cause trypanosomes to burst and die. Species of trypanosome that can infect humans have developed ways to avoid trypanolytic factor uptake or to block the process that leads to lysis.How do the trypanosomes both take up nutrient molecules from the blood and to avoid recognition by antibodies? They are covered by a coat of a protein called VSG. This coat is dynamic with VSG molecules being taken up into the cell together with attached antibodies. The antibodies are degraded and the VSG returned to the surface. The parasite has the ability to express a large number of different VSG molecules, and they can switch which VSG they use to avoid detection by the immune system. The receptor proteins that are used to take up nutrient molecules must bind their cargos in the context of this VSG layer and yet avoid recognition by the immune system.In this proposal we will use a variety of different experimental tools to study one of these receptors - the haptoglobin-haemoglobin receptor (HpHbR). This receptor lies at the heart of a conflict for the parasite. It is involved in the uptake of HpHb into the trypanosome cell, from which the parasite obtains haem molecules to allow it to build its own cellular structures. But it is also a major route for the uptake of trypanolytic factors, leading to parasite death.We will use structural biology methods to understand, in molecular detail, how the receptor recognises its different cargos, including HpHb and trypanolytic factors. We will combine this with cell biology, allowing us to understand how ligand uptake occurs in the context of the parasite surface. This will be the first study that combines structural and cellular experiments to gain insight into a trypanosome receptor, revealing how the trypanosome surface is adapted to allow nutrient uptake while avoiding destruction by the body. It will also show how an uptake route for a toxin molecules functions. This is a route currently used by natural trypanolytic factors and has the potential to be subverted to allow drug and toxin molecules to be specifically targeted to this deadly parasite.