Fungal morphogenesis and environmental response

曲霉，一种霉菌，是一种无性真菌，对人类有好有坏的影响。一些物种用于生物技术，但许多也是机会性的人类病原体，引起病态疾病。丝状真菌细胞，被称为菌丝，被细胞壁包围、支撑和保护，使它们能够穿透和探索周围环境，寻找营养物质。菌丝是管状的，只生长在它们的尖端，在那里它们分泌成壁物质。菌丝壁在细胞和环境之间形成多孔界面。墙体的组成、结构和功能是相互依存的。与所有真菌一样，曲霉的细胞壁约85%是碳水化合物，其中大部分是动物所没有的类型。壁生物合成途径可以成为抗真菌药物的靶点。墙体构件之间的相互作用是墙体结构功能的关键，但尽管已有60多年的研究，但仍有许多未知之处。值得注意的是，真菌对环境变化（如药物）的响应是通过细胞壁完整性网络调节来实现的，而这种细胞壁完整性的调节正是我实验室的研究重点。例如，半乳糖呋喃糖（Gal-f）是一种次要的[~5%]壁糖，用于修饰壁蛋白。我们已经证明，删除Gal-f生物合成的三个步骤中的任何一个都会导致细胞壁结构和功能的重大缺陷，包括：菌丝生长速度和孢子产量降低500倍；细胞壁软、厚、异常；和hyperbranching。然而，减少的Gal-f部分补偿了其他含量较高的，共同调节的壁成分，如α -葡聚糖，其作用尚不清楚。我们发现，在固体培养基中，α -葡聚糖生产基因的缺失不会导致菌落外观或表型的明显变化，但在摇晃的液体培养基中可能导致菌落碎裂。在下一个资助周期中，我们将描述曲霉中的α -葡聚糖合成，并探索壁生物合成途径之间的关系。我们已经表明，曲霉可以在一周内对壁靶药物产生遗传抗性，因此我们呼吁采取紧急措施。我们已经使用这种策略确定了新的壁合成基因，并将在这一至关重要的研究领域扩大努力。

Aspergillus, a mould, is an asexual fungus that impacts humanity for good and ill. Some species are used in biotechnology, but many are also opportunistic human pathogens causing morbid disease. Filamentous fungal cells, called hyphae, are surrounded, supported, and protected by cell walls that enable them to penetrate and explore their surroundings in search of nutrients. Hyphae are tubular and grow only at their tips, where they secrete wall-forming materials. The hyphal wall forms a porous interface between the cell and its environment. Wall composition, structure and function are inter-dependent. As in all fungi, the Aspergillus wall is ~85% carbohydrate, mostly types not found in animals. Wall biosynthesis pathways can be anti-fungal drug targets. Interaction between wall components is key to wall structure-function, but despite >60 years of study, much remains unknown. It is notable that fungi respond to environmental change, e.g. drugs, through cell wall integrity network regulation, and it is this regulation of cell wall integrity that is a focus of research in my laboratory. As an example, galactofuranose (Gal-f) is a minor [~5%] wall sugar that decorates wall proteins. We have shown that deleting any of three steps in Gal-f biosynthesis causes major defects in wall structure-function, including: 500-fold lower hyphal growth rate and spore production; soft, thick and abnormal cell walls; and hyperbranching. However, reduced Gal-f is partly compensated for by higher content of other, co-regulated wall components, such as alpha-glucans, whose roles are yet to be understood. We have found that deletion of genes for alpha-glucan production does not result in an obvious change in appearance, or phenotype, on a solid medium, but may result in colony fragmentation in a shaken liquid medium. In the next funding cycle, we will characterize alpha-glucan synthesis in Aspergillus, and explore relationships between wall biosynthesis pathways. Urgency is called for, as we have shown that Aspergillus can develop heritable resistance to wall-targeting drugs in under a week. We have already identified novel wall-synthesis genes using this strategy, and will extend efforts in this critically important area of research.