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

尽管它们不能传达流行病的属性，但真菌感染是一个日益严重的医学问题。人类感染真菌疾病，造成严重损害或至少与结核病或疟疾一样多的人死亡。其中，烟曲霉菌是引起免疫活性疾病和免疫功能低下宿主疾病的最重要的空气传播真菌，在后一组人群中死亡率高得令人无法接受。烟曲霉对医院病人的威胁可归因于对曲霉病的病理生物学非常不了解。因此，本研究计划的主要目标将是调查孢子(分生孢子)，这是感染的形态类型。我们将特别关注休眠和萌发分生孢子的细胞壁，因为我们已经确定了细胞壁的几个分子，这些分子不仅对调节宿主免疫系统的真菌毒力至关重要，而且对于抵抗外部侮辱也是必不可少的。然而，直到今天，还没有对分生孢子进行全面的生化和遗传分析，这对于了解烟曲霉感染的早期阶段是迫切需要的。为了解决这一根本问题，我们定义了三个任务：在任务1中，将通过蛋白质组和多糖组分析以及结构研究来破译休眠分生孢子的细胞壁成分及其结构组织的图景。在任务2中，将识别在萌发的早期阶段发生的细胞壁修饰和新分泌的蛋白质。在任务3中，将破译来自休眠和萌发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，并将在小鼠感染模型中评估相应突变体的毒力。该联盟由巴斯德研究所的曲霉菌单位(负责人：J.-P.Latgé)和耶拿大学微生物和分子生物学系以及莱布尼茨天然产品研究和感染生物学研究所的分子和应用微生物学系(负责人：A.Brakhage)组成。多年来，这些合作伙伴在烟曲霉的研究方面进行了密集而富有成效的合作，并在生物化学、糖生物学、蛋白质组学、生物信息学、遗传学和感染生物学等方面拥有互补的专业知识，所有这些都是共同努力解决计划任务所需的技术。我们的项目解决了一个重要的悬而未决的问题：空气传播的真菌如何成为人类病原体？对处于休眠和萌发早期的感染性繁殖进行表征，是了解该病的发病机制和开发新的预防和抗真菌治疗方法的关键。本项目对烟曲霉菌的研究结果可望对整个真菌致病科学领域有很大的帮助。

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.