Mechanistic basis of the antifungal potency of the airway epithelium

人类每天吸入成千上万的有毒或传染性颗粒，这对呼吸系统健康构成持续的风险。为了保持健康，我们的肺必须消除这些有害颗粒并保持无菌环境。人类肺部最突出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组成部分，每年在全世界引发300多万种慢性疾病和20万种侵袭性疾病。仅在欧洲，每年与曲霉菌有关的疾病就可能超过200万例。一些严重免疫功能低下的患者，如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，虽然真菌疾病每年造成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。我以前发现，肺上皮细胞可以抓住真菌孢子，吞噬它们并杀死它们，并且这个过程在患有真菌性肺病风险较高的患者的肺细胞中发生了改变，例如慢性阻塞性肺病（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的相互作用，我的目标是确定人类肺的健康上皮细胞如何识别真菌孢子并杀死它们，这个过程如何影响肺环境中免疫细胞之间的交流，以及这一过程在真菌病高危患者的细胞中是如何改变的。因此，预防烟曲霉菌感染和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预防对其他空气传播的病原体和污染物引起的肺部疾病的危险反应。

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.