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

锥虫触珠蛋白-血红蛋白受体如何与营养物质和免疫分子相互作用？

• 批准号: MR/L008246/1
• 负责人: Mark Carrington
• 金额: $ 90.78万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL008246%2F1
• 关键词: How; does; trypanosome; haptoglobin; hemoglobin

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.

锥虫是单细胞寄生虫，在撒哈拉以南非洲地区引起严重疾病。它们感染人类，导致非洲昏睡病。它们还感染多种家畜，包括牛，导致疾病，降低粮食生产能力。锥虫在人类或动物宿主的血液中生存和分裂。为了在这种环境中生存，它们具有高度适应的细胞表面。这使得它们能够从血液中吸收营养分子，在生长和分裂时将其用作能量来源或建筑材料。然而，这也让他们陷入危险之中。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消灭。人体还含有几种称为锥虫分解因子的蛋白质复合物。如果被寄生虫吸收，就会导致锥虫破裂并死亡。可以感染人类的​​锥虫种类已经开发出多种方法来避免锥虫分解因子的吸收或阻止导致裂解的过程。锥虫如何从血液中吸收营养分子并避免被抗体识别？它们被一层称为 VSG 的蛋白质外壳覆盖。该外壳是动态的，VSG 分子与附着的抗体一起被吸收到细胞中。抗体被降解，VSG 返回表面。这种寄生虫能够表达大量不同的 VSG 分子，并且它们可以切换使用哪种 VSG 以避免被免疫系统检测到。用于吸收营养分子的受体蛋白必须在该 VSG 层中结合其货物，同时避免被免疫系统识别。在本提案中，我们将使用各种不同的实验工具来研究其中一种受体 - 触珠蛋白-血红蛋白受体 (HpHbR)。这种受体是寄生虫冲突的核心。它参与锥虫细胞摄取 HpHb，寄生虫从中获得血红素分子，使其能够构建自己的细胞结构。但这也是吸收锥虫分解因子并导致寄生虫死亡的主要途径。我们将使用结构生物学方法从分子细节上了解受体如何识别其不同的货物，包括 HpHb 和锥虫分解因子。我们将把它与细胞生物学结合起来，使我们能够了解配体摄取在寄生虫表面的情况下是如何发生的。这将是第一项结合结构和细胞实验来深入了解锥虫受体的研究，揭示锥虫表面如何适应吸收营养，同时避免被身体破坏。它还将展示毒素分子的摄取途径如何发挥作用。这是天然锥虫分解因子目前使用的一条途径，并且有可能被颠覆，使药物和毒素分子专门针对这种致命的寄生虫。

项目成果

A Receptor's Tale: An Eon in the Life of a Trypanosome Receptor.

一个受体的故事：锥虫受体生命中的eon。

• DOI: 10.1371/journal.ppat.1006055
• 发表时间: 2017-01
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Higgins MK;Lane-Serff H;MacGregor P;Carrington M
• 通讯作者: Carrington M

A single dose of antibody-drug conjugate cures a stage 1 model of African trypanosomiasis

单剂抗体药物偶联物治愈非洲锥虫病第一阶段模型

• DOI: 10.1101/547208
• 发表时间: 2019
• 作者: MacGregor P

How Does the VSG Coat of Bloodstream Form African Trypanosomes Interact with External Proteins?

VSG的血液涂层如何形成非洲锥虫体与外部蛋白质相互作用？

• DOI: 10.1371/journal.ppat.1005259
• 发表时间: 2015-12
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Schwede A;Macleod OJ;MacGregor P;Carrington M
• 通讯作者: Carrington M

Structural basis for ligand and innate immunity factor uptake by the trypanosome haptoglobin-haemoglobin receptor.

• DOI: 10.7554/elife.05553
• 发表时间: 2014-12-12
• 期刊: eLife
• 影响因子: 7.7
• 作者: Lane-Serff H;MacGregor P;Lowe ED;Carrington M;Higgins MK
• 通讯作者: Higgins MK

A Receptor's Tale: An Eon in the Life of a Trypanosome Receptor

受体的故事：锥虫受体的亿万年生命

• DOI: 10.17863/cam.7688
• 发表时间: 2017
• 作者: Higgins M