THE ROLE OF EXTRACELLULAR VESICLES IN REGULATING DIVISION OF LABOUR IN FUNGI

许多动物物种使用团队合作，以便通过分工最大限度地适应：例如，通过分配守卫职责和采集食物的职责给群居昆虫中的不同个体。然而，最近一个令人惊讶的发现是，单细胞微生物也能够进行分工。此外，这种行为通常是细菌产生抗菌素耐药性等重要过程的基础。我们最近在致命的真菌病原体隐球菌中发现了一种新的分工行为。进入寄主后，单个真菌细胞相互交流，以适应两种不同的命运：一些个体停止生长，成为静止的“保卫细胞”，然后保护其他“增殖”的个体不被宿主杀死。这使得真菌能够快速生长并压倒宿主；这是任何一种真菌细胞类型都无法单独实现的。这种分工在分子水平上发生的机制完全未知。然而，我们最近的数据表明，它所需的细胞间通信是由细胞外小泡进行的，细胞外小泡充当远程“信鸽”，使真菌细胞能够在长距离协调它们的行为。因此，这项提议的目的是首次剖析这种新的毒力机制的性质：1.发现细胞外小泡如何协调真菌的行为2。表征这些囊泡的内容物3。确定这些小泡是如何在真菌和它们周围的宿主细胞之间运输的。揭示宿主细胞对这种真菌操作的反应。通过这样做，我们的目标是揭示一种全新的人类和动物疾病的发病机制。此外，由于i)分工机制在各种微生物中运作，以及ii)细胞外小泡已知由大量细菌和真菌物种排出，我们将在本项目中揭示的过程可能为理解整个微生物学领域的分工提供一个广泛的范式。

Many animal species use teamwork in order to maximize fitness through Division of Labour: for instance, via the allocation of guard duties and food gathering duties to different individuals in social insects. However, a recent and surprising discovery has been that single-celled microbes are also capable of Division of Labour. Moreover, such behaviours often underlie important processes such as antimicrobial resistance in bacteria.We have recently discovered a novel Division of Labour behaviour in the fatal fungal pathogen Cryptococcus gattii. Upon entry into the host, individual fungal cells communicate in order to adopt two different fates: some individuals stop growing and become quiescent "guard cells", which then protect the other "proliferative" individuals from being killed by the host. This enables the fungus to grow rapidly and overwhelm the host; something that neither fungal cell type can achieve alone.The mechanism by which this Division of Labour occurs at the molecular level is completely unknown. However, we have recent data demonstrating that the cell-to-cell communication it entails is carried out by extracellular vesicles, which act as long-distance "carrier pigeons" to enable fungal cells to coordinate their behaviour over large distances. The aim of this proposal is therefore to dissect, for the first time, the nature of this novel virulence mechanism by:1. discovering how extracellular vesicles coordinate fungal behaviour2. characterizing the contents of these vesicles3. identifying how these vesicles are transported between fungi and their surrounding host cells4. revealing how host cells respond to this fungal manipulation.In doing so, we aim to reveal a completely new type of pathogenesis mechanism in an important human and animal disease. In addition, since i) Division of Labour mechanisms operate in a diverse range of microbes, and ii) extracellular vesicles are known to be shed by a large number of bacterial and fungal species, it is possible that the processes we will unveil within this project may provide a broad paradigm for understanding Division of Labour across the full breadth of microbiology.