How do African trypanosomes invade host tissues?

非洲锥虫是如何入侵宿主组织的？非洲锥虫病的特点是血液中最初出现一波寄生虫血症，然后是中枢神经系统的入侵。最近的研究强调了组织和器官作为潜在的储存库和保护环境对形成寄生虫血症、耐药性和寄生虫传播的特征波的重要性(Trindade等人，2016；Beaver等人，2022)。然而，对组织间的动态流动、它们在血流再次入侵中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)。最近的研究发现了一种非传统的分泌自噬相关途径，称为溶酶体胞吐作用，它与分泌肽酶/水解酶有关，使线虫能够入侵宿主细胞(Naegeli等人，2017年)。该项目的目的是了解通过溶酶体胞吞作用分泌的肽酶如何促进布鲁氏毛滴虫的寄生虫发展和宿主组织入侵。这项研究将提供对寄生虫的生命周期和疾病发展的理解，在这些过程中，隔间可能起到作用。这将需要使用一系列尖端技术，例如体内纵向感染、CRISPR/Cas9基因编辑、定量蛋白质组学、邻近标记、酶分析以及体内/体外成像。这位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-病原体相互作用方面的专业知识。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300万人死亡和3500万剂杀锥虫病药物用于牛(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，这项研究疾病进展的分子机制的项目有可能为未来急需的筛查/诊断(寄生虫“隐藏”在器官中)和战斗策略提供翻译开发。此外，调节溶酶体胞吐及其功能的分子机制仍然是真核生物生物学中的一个主要谜团，因此这个项目将提供对寄生虫如何在体内持续和发展的关键了解。工作环境：我们的实验室提供了一个支持和合作的环境，博士生可以在其中扩大他们的范围和学习新技术。这位博士生还将加入约克生物医学研究所的一个研究团队，研究导致非洲锥虫病和利什曼病的寄生虫的细胞过程。生物系以其研究而享誉国际，并努力提供一个工作环境，使所有教职员工和学生都能充分、蓬勃和出色地做出贡献。目标：1)调查溶酶体胞吐途径释放多肽酶。2)揭示多肽酶在哺乳动物宿主组织入侵中的作用。3)揭示哺乳动物器官的功能，以了解寄生虫感染和发育的动态。新奇：这项研究将提供对寄生虫的生活史和疾病进展的了解，这些疾病由溶酶体胞吐和肽酶分泌调节。它将建立一个寄生虫蛋白在不同组织中表达的图谱，并揭示它们在疾病进展和传播中的作用。

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.