The molecular basis and evolution of host-parasite interactions in African trypanosomes

非洲锥虫是一种单细胞寄生虫，生活在撒哈拉以南非洲的哺乳动物的血液中，通过采采蝇的叮咬在哺乳动物之间传播。几种锥虫会导致牛和其他牲畜患病，导致农民失去生产力。这种疾病在受影响地区是一个巨大的经济负担，导致非洲农村家庭的生活机会减少。这些锥虫物种中的一种能够感染人类并导致一种致命的疾病。目前，药物治疗既低效又有毒。这种寄生虫从宿主那里获取营养，避免被宿主免疫系统杀死，并适应它们可以感染的不同哺乳动物。通过我的研究，我最终想要了解并干预锥虫与它们的哺乳动物宿主相互作用的方式。如果你向下看显微镜下感染锥虫的哺乳动物的血液，你会看到这些单细胞寄生虫在红细胞之间游泳。它们不会躲避旨在防止感染的宿主免疫防御系统。相反，它们有一个特殊的、高度适应的细胞表面，主要由一种重要的蛋白质组成，使它们能够防御攻击。然而，它们的表面并不是专门用于防御的。它们还必须相互交流，在不损害它们的防御能力的情况下为它们的生长获取营养，这需要其他蛋白质分子。这究竟是如何实现的还不完全清楚：它们是将其他重要的蛋白质隐藏在它们的表面，还是在任何时候它们的表面都只有很少的蛋白质？我将跟踪已知的营养受体的位置和运动来回答这些问题，并测量这些受体的可及性。这项工作将主要在英国剑桥大学进行，但也将有牛津大学(英国)和维尔茨堡大学(德国)的科学家参与。不同的锥虫物种以不同的方式与它们的哺乳动物宿主相互作用，在拟议的研究中，我的目标是了解这一分子基础。我将比较多个物种的细胞表面：相似性告诉我们锥虫感染哺乳动物所需的重要因素；差异使我们能够了解这些物种的进化方式以及为什么它们会导致不同的疾病症状。大多数锥虫研究集中在实验室培养的菌株上，这些菌株不同于今天在非洲牛身上发现的锥虫。我的研究将比较实验室锥体和加纳新鲜分离的牛的锥体之间的差异，以揭示锥体生物学的一些方面，这些方面对哺乳动物的传染性很重要，否则无法使用实验室菌株来识别。这项工作将与加纳大学(加纳)的研究人员合作，将有助于更好地了解哺乳动物中锥虫的传染性及其如何导致疾病。这项工作将开始解决非洲锥虫中宿主-寄生虫相互作用的分子生物学和进化，以及这些因素如何影响它们感染哺乳动物并导致疾病的能力的长期问题。

African trypanosomes are single-celled parasites that live in the bloodstream of mammals in sub-Saharan Africa and are passed between mammals though the bite of the tsetse fly. Several species of trypanosome lead to disease in cattle and other livestock, resulting in loss of productivity for farmers. The disease is a huge economic burden in affected areas, leading to reduced life chances for families in rural Africa. One of these trypanosome species is able to infect humans and causes a lethal disease. Currently drug treatments are inefficient and toxic. The parasite acquires nutrients from their host, avoid killing by the host immune system and adapt to the different mammals they can infect. Through my research I would ultimately like to understand, and then interfere, with the way in which trypanosomes interact with their mammalian hosts.If you look down a microscope at the blood from a trypanosome-infected mammal, you would see these single-celled parasites, swimming amongst the red blood cells. They do not hide from the host immune defences that are designed to prevent infections. Instead they have a specialised and highly adapted cell surface mostly composed of an important protein that allows them defend themselves against attack. However, their surface is not dedicated solely to defence. They must also communicate with one another and acquire nutrients for their growth without compromising their defence which requires other protein molecules. Exactly how this is achieved is not understood fully: do they hide the other important proteins at their surface or do they have very few on the surface at any one time? I will follow the position and movements of known nutrient receptors to answer these questions as well as measure how accessible these receptors. This work will primarily be carried out at the University of Cambridge (UK) but will also involve scientists based at the University of Oxford (UK) and the University of Würzburg (Germany).Different trypanosome species interact with their mammalian hosts in different ways and in the proposed research I aim to understand the molecular basis for this. I will compare the cell surface of multiple species: the similarities tells us the important factors required for trypanosomes to infect mammals in general; the differences allows us to understand the way these species evolved and why they cause distinct disease symptoms. Most trypanosome research focusses on laboratory grown strains that are different to the trypanosomes found in cattle in Africa today. My research will compare the differences between laboratory trypanosomes and those freshly isolated from cattle in Ghana in order to reveal aspects of the trypanosome biology that are important for infectivity in mammals that would otherwise not be identified using laboratory strains. This work would be in collaboration with researchers at the University of Ghana (Ghana) and would lead to a better understanding of the infectivity of trypanosomes in mammals and how that contributes to disease.This work will begin to address long-term questions about the molecular biology and evolution of host-parasite interactions in African trypanosomes and how these affect their ability to infect and cause disease in mammals, such as humans and livestock.