Mechanistic basis of the antifungal potency of the airway epithelium

人类每天吸入数以千计的有毒或传染性颗粒，这对呼吸健康构成持续的风险。为了保持健康，我们的肺部必须清除这些有毒颗粒物，并保持无菌环境。人类肺部最主要的真菌病原体烟曲霉的空气传播孢子是我们呼吸的空气的主要成分，每年在全球引发300多万种慢性和20万种侵袭性疾病。仅在欧洲，与曲霉菌相关的疾病每年的数量就可能超过200万。一些免疫功能严重受损的患者，比如那些接受骨髓移植的患者，一旦感染真菌，存活率只有10%。值得注意的是，尽管真菌疾病每年导致的死亡人数超过结核病或疟疾，但我们仍然缺乏有效的药物来治疗它们。我之前发现，肺上皮细胞可以抓住真菌孢子，吞噬它们，并杀死它们，而且这个过程在真菌肺病风险较高的患者的肺细胞中发生了变化，例如慢性阻塞性肺疾病(COPD)患者。使用最先进的技术来研究基因工程荧光真菌突变株和突变肺细胞之间的相互作用，我的目标是确定健康的人类肺上皮细胞如何识别并杀死真菌孢子，这一过程如何影响肺部环境中免疫细胞之间的通信，以及这一过程如何在有较高真菌疾病风险的患者的细胞中改变。详细了解上皮细胞如何帮助清除吸入的烟曲霉菌并维持健康的肺部环境，将使我们能够设计新的抗真菌疗法，并可能导致更好的方法来防止对其他空气传播病原体和导致肺部疾病的污染物的危险反应。

Human beings inhale many thousands of toxic or infectious particles daily, which represent a continuous risk to respiratory health. To remain healthy, our lungs must eliminate these noxious particles and maintain a sterile environment. Airborne spores of the most prominent fungal pathogen of human lungs, Aspergillus fumigatus, are a major component of the air we breathe and initiate more than 3 million chronic and 200,000 invasive diseases annually, worldwide. In European alone aspergillus-related diseases are likely to exceed 2 million in number per year. Some groups of severely immunocompromised patients, such those undergoing bone marrow transplants have just a 10% survival rate once a fungal infection is contracted. Remarkably, while fungal diseases cause more deaths annually than tuberculosis or malaria, we still lack effective drugs to treat them. I have previously found that the lung epithelium can grab fungal spores, swallow them up, and kill them and that this process is altered in lung cells from patients having a higher risk of fungal lung disease, such as patients with chronic obstructive pulmonary disease (COPD). Using state-of-the-art technologies to study the interaction of genetically-engineered fluorescent fungal mutant strains and mutant lungs cells, I aim to determine how healthy epithelial cells of the human lung recognise fungal spores and kill them, how this process might influence communication between immune cells in the lung environment, and how this process is altered in cells from patients that have a higher risk of fungal disease.A detailed understanding of how epithelial cells contribute to clear inhaled A. fumigatus and maintain a healthy lung environment will enable us to design new antifungal therapies, and potentially lead to better ways of preventing dangerous responses to other airborne pathogens and pollutants causing lung diseases.