How do African trypanosomes invade host tissues?

非洲锥虫如何侵入宿主组织？

• 批准号: 2888919
• 金额: --
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2888919
• 关键词: How; do; African; trypanosomes; invade

How do African trypanosomes invade host tissues?African trypanosomiasis is characterised by initial waves of parasitaemia in the bloodstream, followed by invasion of the central nervous system. Recent studies highlighted the importance of tissues and organs as a potential reservoir and protective environment for the creation of the characteristic waves of parasitaemia, drug resistance and parasite transmission (Trindade et al., 2016; Beaver et al., 2022). However, little is known about the dynamic flux between tissues, their roles for the bloodstream re-invasion and their influence on the parasites' life cycle (Cayla et al., 2019). Recent studies have identified an unconventional secretory autophagy-related pathway, called lysosome exocytosis, that has been implicated in secretion peptidases/hydrolases enabling host cell invasion by the worm C. elegans (Naegeli et al., 2017). The aim of the project is to understand how peptidase secretion through lysosome exocytosis enables parasite development and host tissue invasion of the T. brucei. This research will provide an understanding of the parasite's life cycle and disease progression where compartments may play a role. This will require the use of a range of cutting-edge techniques such as longitudinal in vivo infection, CRISPR/Cas9 gene editing, quantitative proteomics, proximity-labelling, enzymatic assays and both in vivo/vitro imaging. The PhD student will gain expertise in trypanosome biology, cell-signalling regulation, proteomics, microscopy and host-pathogens interactions. Impact:The economic losses in cattle production dgue to African trypanosomiasis are in the range of US$1.0-1.2 billion, with about 3 million deaths and 35 million doses of trypanocidal drugs administered on cattle per year (Bekele, 2015). In humans, this disease is still considered as a neglected tropical disease. Therefore, this project investigating the molecular mechanisms responsible for the disease progression has a potential for translational development for much needed future screening/diagnosis (parasites "hiding" in organs) and combative strategies. In addition, the molecular mechanisms regulating lysosome exocytosis and its function remain a major mystery in eukaryote biology and this project will therefore provide critical understanding of how parasites persist and develop in vivo.Working environment:Our laboratories provide a supportive and collaborative environment in which the PhD student can expand their range and learn new techniques. The PhD student will also join a team of researchers in the York Biomedical Research Institute investigating cellular processes in parasites that cause African trypanosomiasis and leishmaniasis. The Department of Biology is renowned internationally for its research and strives to provide a working environment which allows all staff and students to contribute fully, flourish, and excel.Objectives:1) Investigating the release of peptidases by the lysosome exocytosis pathway.2) Revealing the role of peptidases for host tissue invasion in the mammalian host.3) Shedding light on the function of mammal organs for the dynamic of the parasite infection and development.Novelty:This research will provide understanding of parasite's life cycle and disease progression regulated by lysosome exocytosis and peptidase secretion. It will build an atlas of parasite protein expression within the different tissues and reveal their function for the disease progression and transmission.

非洲锥虫如何侵入宿主组织？非洲锥虫病的特点是血液中的寄生虫血症的初始波，然后入侵中枢神经系统。最近的研究强调了组织和器官作为产生寄生虫病、耐药性和寄生虫传播的特征波的潜在储存库和保护环境的重要性（特林达德等人，2016; Beaver等人，2022年）。然而，关于组织之间的动态通量、它们对血流再侵入的作用以及它们对寄生虫生命周期的影响知之甚少（Cayla等人，2019年）。最近的研究已经确定了一种非常规的分泌性自噬相关途径，称为溶酶体胞吐，其涉及分泌肽酶/水解酶，使得蠕虫C.线虫（Naegeli等人，2017年）。该项目的目的是了解如何通过溶酶体胞吐分泌肽酶使寄生虫的发展和宿主组织入侵的T。布鲁塞。这项研究将提供对寄生虫生命周期和疾病进展的理解，其中隔间可能发挥作用。这将需要使用一系列尖端技术，如纵向体内感染，CRISPR/Cas9基因编辑，定量蛋白质组学，邻近标记，酶测定和体内/体外成像。博士生将获得锥虫生物学，细胞信号调节，蛋白质组学，显微镜和宿主-病原体相互作用的专业知识。影响：非洲锥虫病给牛生产造成的经济损失在10 - 12亿美元之间，每年约有300万人死亡，3500万剂杀锥虫药物用于牛（Bekele，2015）。在人类中，这种疾病仍然被认为是一种被忽视的热带疾病。因此，该项目研究了导致疾病进展的分子机制，具有转化发展的潜力，可用于未来急需的筛查/诊断（寄生虫“隐藏”在器官中）和战斗策略。此外，调节溶酶体胞吐作用及其功能的分子机制仍然是真核生物学中的一个主要谜团，因此该项目将提供对寄生虫如何在体内持续和发展的关键理解。工作环境：我们的实验室提供了一个支持和协作的环境，博士生可以在其中扩大他们的范围并学习新技术。博士生还将加入约克生物医学研究所的一个研究小组，研究引起非洲锥虫病和利什曼病的寄生虫的细胞过程。生物学系以其研究而享誉国际，并致力于提供一个让所有教职员工和学生都能充分贡献、蓬勃发展和出类拔萃的工作环境。目的：1）研究通过溶酶体胞吐途径释放的肽酶。2）揭示肽酶在宿主组织侵入哺乳动物宿主中的作用。3）阐明哺乳动物器官在寄生虫感染和发育动态中的功能。新奇：这项研究将有助于了解寄生虫的生活史和疾病进展的调节溶酶体胞吐和肽酶分泌。它将建立不同组织内寄生虫蛋白表达的图谱，并揭示它们在疾病进展和传播中的功能。