Aspergillus terreus as a cause of invasive aspergillosis: Impact of secondary metabolites on pathogenesis

土曲霉是侵袭性曲霉病的病因：次生代谢产物对发病机制的影响

• 批准号: 150413556
• 负责人: Professor Dr. Matthias Brock
• 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: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/150413556?language=en
• 关键词: Aspergillus; terreus; cause; invasive; aspergillosis

Oral application of culture extracts from the emerging pathogenic fungus Aspergillus terreus causes morphological changes of liver cells, indicating the production of mycotoxins. Consistently, our preliminary investigations on murine infection models for invasive aspergillosis revealed major hepatic lesions in mice suffering from A. terreus infections. Although A. terreus is less frequently isolated from patients with invasive aspergillosis than A. fumigatus, the resistance against the potent antifungal drug amphotericin B hampers treatment of A. terreus infections and leads to up to 100% mortality. Despite the severe outcome of A. terreus infections, pathogenesis has hardly been studied. To elucidate the impact of the production of secondary metabolites on A. terreus virulence, infection models will be established, which allow monitoring the temporal and spatial development of the infection under in vivo conditions by using bioluminescent A. terreus strains. Microarrays covering representatives from all secondary metabolite biosynthesis clusters will be used to correlate the progression of infection with secondary metabolite production. The use of reporter strains will allow following the metabolite production under in vitro conditions to enable the identification, purification and characterisation of the respective compounds. By studying the virulence of mutants defective in secondary metabolite production we expect to gain new insights into the pathophysiology of A. terreus.

口服新出现的致病真菌土曲霉的培养物可引起肝细胞的形态变化，表明产生了真菌毒素。我们对侵袭性曲霉病小鼠感染模型的初步研究一直显示，感染土曲霉的小鼠出现了主要的肝脏损害。尽管与烟曲霉菌相比，侵袭性曲霉病患者中分离出的Terreus较少，但对有效的抗真菌药物两性霉素B的耐药性阻碍了Terreus感染的治疗，并导致高达100%的死亡率。尽管土曲霉感染的后果很严重，但其发病机制几乎没有研究过。为了阐明次生代谢物的产生对Terreus毒力的影响，将建立感染模型，利用生物发光的A.terreus菌株在体内条件下监测感染的时空发展。覆盖所有次级代谢物生物合成集群的代表的微阵列将被用来将感染的进展与次级代谢物的产生联系起来。报告菌株的使用将允许在体外条件下跟踪代谢物的产生，从而能够识别、纯化和表征各自的化合物。通过研究次生代谢物产生缺陷突变株的毒力，我们有望对土曲霉的病理生理学有新的认识。