Defining the role of phosphate metabolism in promoting stress resistance and virulence in fungal pathogens

病原真菌适应不同寄主生态位内遇到的压力的能力对其毒力至关重要。最近，我们发现由Pho4转录因子调控的磷酸盐稳态对于真菌病原体白色念珠菌在感染过程中抵抗多种生理上重要的应激至关重要。此外，我们发现pho4 δ细胞表现出的许多应激敏感表型，如对金属阳离子和超氧化物胁迫，与磷酸盐代谢对金属稳态的影响有关。由于Pho4在白色念珠菌的发病机制中至关重要，这些发现为代谢适应如何促进白色念珠菌在面对宿主施加的压力时的生存提供了新的见解。然而，我们对白色念珠菌中Pho4的调控知之甚少，也不知道细胞内磷酸盐水平影响金属稳态的机制，从而导致对各种胁迫的抵抗。在这个项目中，我们将定义白色念珠菌磷酸盐获取策略的调控网络，并研究磷酸盐与金属稳态和抗逆性的联系机制。这是很重要的，因为我们的数据强烈表明，在致病真菌的磷酸盐获取策略的扰动可能代表一个新的治疗策略，以减轻毒力。因此，该项目符合BBSRC“基础生物科学支撑健康”的战略研究重点。我们预测，在白色念珠菌中产生的研究成果也可以转移到重要的植物真菌病原体上。在稻瘟病菌和玉米黑穗病菌中，抗逆性和金属获取策略也是重要的毒力决定因素。鉴于这类病原体对粮食安全的威胁日益严重，本项目也适用于“农业与粮食安全”的研究重点。

The ability of pathogenic fungi to adapt to stresses encountered within different host niches is essential for virulence. Recently, we have found that phosphate homeostasis, regulated by the Pho4 transcription factor, is vital for the resistance of the fungal pathogen, Candida albicans, to diverse and physiologically important stresses encountered during infection. Furthermore, we have found that many of the stress-sensitive phenotypes exhibited by pho4 delta cells, such as to metal cation and superoxide stresses, relate to the impact of phosphate metabolism on metal homeostasis. As Pho4 is vital for C. albicans pathogenesis, these findings provide new insight into how metabolic adaptation promotes C. albicans survival in the face of host-imposed stresses. However we know little regarding the regulation of Pho4 in C. albicans, or the mechanism(s) by which intracellular phosphate levels impact on metal homeostasis resulting in resistance to diverse stresses. In this project, we will define the regulatory network underlying phosphate acquisition strategies in C. albicans and investigate the mechanisms linking phosphate to metal homeostasis and stress resistance. This is important as our data strongly indicates that perturbation of phosphate acquisition strategies in pathogenic fungi could represent a novel therapeutic strategy to attenuate virulence. The project therefore fits with the BBSRC's strategic research priority of "Basic bioscience underpinning health". We predict that the research outcomes generated in C. albicans can also be transferred onto important plant fungal pathogens. Stress tolerance and metal acquisition strategies are also important virulence determinants in many plant pathogens such as the rice blast fungus Magnaporthe grisea and the corn smut fungus Ustilago maydis. Given the increasing threat to food security by such pathogens this project also applies to the research priority "Agriculture and food security".