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

口服新出现的病原真菌土曲霉的培养提取物会引起肝细胞的形态变化，表明真菌毒素的产生。与此一致的是，我们对侵袭性曲霉病小鼠感染模型的初步研究显示，受土曲霉感染的小鼠肝脏出现重大病变。尽管与烟曲霉相比，从侵袭性曲霉病患者中分离出的地芽孢杆菌较少，但对强效抗真菌药物两性霉素B的耐药性阻碍了对地芽孢杆菌感染的治疗，并导致高达100%的死亡率。尽管地芽孢杆菌感染的严重后果，发病机制几乎没有研究。为了阐明次生代谢物的产生对A. 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。微阵列涵盖了所有次生代谢物生物合成集群的代表，将用于将感染的进展与次生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，从而能够鉴定、纯化和表征各自的化合物。通过研究次生代谢物产生缺陷的突变体的毒力，我们期望对土刺的病理生理有新的认识。

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.