AfuInf - Proteome and polysaccharidome of Aspergillus fumigatus at early stage of infection

AfuInf - 感染早期烟曲霉的蛋白质组和多糖组

基本信息

批准号：
316898429
负责人：
Professor Dr. Axel Brakhage, Ph.D.
金额：
--
依托单位：
Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. Hans-Knöll-Institut
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/316898429?language=en
关键词：
AfuInf Proteome polysaccharidome Aspergillus fumigatus

项目摘要

Although they do not convey the attribute epidemics, fungal infections are an increasingly significant medical problem. Humans contract fungal diseases that cause severe damage or kill at least as many people as tuberculosis or malaria. Among them, Aspergillus fumigatus is the most important airborne fungal mould that is responsible for diseases in immunocompetent as well as immunocompromised hosts with unacceptably high mortality rates in the latter cohort. The threat posed by A. fumigatus to hospital patients is attributable to a very poor understanding of the pathobiology of aspergillosis. Therefore, the major objective of this research program will be to investigate the spore (conidium), which is the infectious morphotype. A special focus will be on the cell wall of the resting and germinating conidium since we have identified several molecules of the cell wall, which are essential either for fungal virulence by modulating the host immune system but also for resistance against external insults. Until today, however, there is no comprehensive biochemical and genetic analysis of conidia, which is urgently required to understand the early stages of A. fumigatus infection. To address this fundamental problem, we have defined 3 tasks:In task 1, the landscape of the cell wall components of the dormant conidium and their structural organization will be deciphered by proteome and polysaccharidome analyses as well as structural studies. In task 2, the cell wall modifications and newly secreted proteins occurring during the early stages of germination will be identified. In task 3, the effect of cell wall-associated components from resting and germinating conidia on macrophages including the analysis of the phagolysosomal proteome will be deciphered and virulence of the respective mutants will be evaluated in a mouse infection model.The consortium is composed of the Aspergillus unit of the Institut Pasteur (head: J.-P. Latgé) and the Department of Microbiology and Molecular Biology, University of Jena and the Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (head: A. Brakhage). Since many years, these partners have been having an intense and fruitful collaboration on the study of A. fumigatus and have complementary expertise in, e.g., biochemistry, glycobiology, proteomics, bioinformatics, genetics and infection biology, all technologies required to work together to tackle the planned tasks.Our project addresses the important unanswered question: How can an airborne fungus become a human pathogen? Characterizing the infectious propagules in their dormant and early germinating stage is a key for the understanding of the establishment of the disease and the development of new prophylactic and antifungal therapies. Results obtained during this project with A. fumigatus can be expected to be of great benefit for the whole scientific field of fungal pathogenicity.

尽管它们不具有流行病的属性，但真菌感染是一个日益重要的医学问题，人类感染的真菌疾病造成的严重损害或死亡人数至少与结核病或疟疾一样多，其中烟曲霉是最重要的空气传播真菌。烟曲霉对医院患者造成的威胁归因于免疫功能正常和免疫功能低下的宿主的疾病，并且后者的死亡率高得令人无法接受。对曲霉病的病理学了解甚少，因此，该研究计划的主要目标是研究孢子（分生孢子），这是一种传染性形态类型，特别关注静止和发芽的分生孢子的细胞壁。因为我们已经鉴定了细胞壁的几种分子，它们对于调节宿主免疫系统的真菌毒力以及抵抗外部损伤至关重要，但是直到今天，还没有全面的生化研究。和分析分生孢子，这对于了解烟曲霉感染的早期阶段是迫切需要的。为了解决这个基本问题，我们定义了 3 个任务：在任务 1 中，休眠分生孢子的细胞壁成分及其结构。在任务 2 中，将通过蛋白质组和多糖组分析以及结构研究来破译组织，在任务 3 中，将鉴定在发芽早期阶段发生的细胞壁修饰和新分泌的蛋白质。休眠和发芽分生孢子的细胞壁相关成分对巨噬细胞的影响，包括吞噬溶酶体蛋白质组的分析将被破译，并且将在小鼠感染模型中评估各个突变体的毒力。该联合体由曲霉属单位组成巴斯德研究所（负责人：J.-P. Latgé）、耶拿大学微生物学和分子生物学系以及莱布尼茨天然产物研究和感染生物学研究所分子与应用微生物学（负责人：A. Brakhage）多年来，这些合作伙伴一直在烟曲霉的研究方面进行了密切而富有成效的合作，并在以下领域拥有互补的专业知识。、生物化学、糖生物学、蛋白质组学、生物信息学、遗传学和感染生物学，以及共同完成计划任务所需的所有技术。我们的项目解决了重要的未解答的问题：空气中的真菌如何成为人类病原体？表征休眠和早期发芽阶段的传染性繁殖体是了解该疾病的形成和开发新的预防和抗真菌疗法的关键。预计烟曲霉将为整个真菌致病性科学领域带来巨大益处。