Defining the single-cell transcriptional and immunological atlas driving antifungal mucosal responses

定义驱动抗真菌粘膜反应的单细胞转录和免疫图谱

• 批准号: 2764561
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2764561
• 关键词: Defining; single; cell; transcriptional; immunological

Inhalation of Aspergillus fumigatus spores cause >3,000,000 chronic and >200,000 invasive diseases annually worldwide. Invasive aspergillosis carries a 50% mortality rate overall, but mortality rate approaches 100% if diagnosis is delayed or missed and it is >75% in certain cohorts of patients. Additionally, current mortality approaches 100% for infections with azole-resistant isolates, which have increased by 40% since 2006. Thus, there is an urgent need for the development of novel strategies for the clinical management of fungal infection.Previous work from the Bertuzzi's group has demonstrated that airway epithelial cells (AECs) efficiently kill A. fumigatus spores upon uptake and that this process is altered in patients with chronic obstructive pulmonary disease (COPD), a well-known risk factor for debilitating fungal lung disease. Therefore, the overarching hypothesis of their work is that AECs critically contribute to healthy clearance of inhaled A. fumigatus spores and that dysregulation of protective AEC responses represents a potent driver of aspergillus-related diseases. Using state-of-the-art single-cell technologies, we now wish to define the transcriptional and immunological responses at the base of effective and dysfunctional clearance of A. fumigatus spores and concomitant homeostasis of airway inflammatory responses, to determine how healthy AECs recognize and kill A. fumigatus and how this process influences immune responses and is dysregulated in disease. To this end, we propose to perform first-in-field transcriptional and immunological analyses of the A. fumigatus-AEC interaction in vitro, ex vivo and in primary AECs from healthy donors and COPD patients stratified according to disease severity.With the overall aim of obtaining a mechanistic understanding of the antifungal potency of the airway epithelium and its dysfunction in disease, this research ultimately aims to inform the identification of immune-modulators to facilitate clinical management of these and other lethal respiratory infections and ultimately reduce their disease burden in humans.

吸入烟曲霉孢子每年在全世界造成300万例慢性疾病和20万例侵袭性疾病。侵袭性曲霉病总体死亡率为50%，但如果诊断延迟或漏诊，死亡率接近100%，在某些患者队列中死亡率为75%左右。此外，目前抗唑分离株感染的死亡率接近100%，自2006年以来增加了40%。因此，迫切需要为真菌感染的临床管理开发新的策略。Bertuzzi小组之前的工作已经证明，气道上皮细胞（AECs）在摄取后有效地杀死烟曲霉孢子，并且这一过程在慢性阻塞性肺疾病（COPD）患者中发生改变，慢性阻塞性肺疾病是众所周知的真菌肺病的危险因素。因此，他们工作的总体假设是AEC对吸入的烟曲霉孢子的健康清除至关重要，并且AEC保护性反应的失调是曲霉相关疾病的有力驱动因素。利用最先进的单细胞技术，我们现在希望在烟曲霉孢子的有效和功能失调清除以及伴随的气道炎症反应的稳态的基础上定义转录和免疫反应，以确定健康的aec如何识别和杀死烟曲霉，以及这一过程如何影响免疫反应并在疾病中失调。为此，我们建议在体外、离体和来自健康供体和COPD患者的原发性aec中对烟熏假单胞菌- aec相互作用进行首次现场转录和免疫学分析。本研究的总体目标是了解气道上皮的抗真菌能力及其在疾病中的功能障碍的机制，最终目的是为免疫调节剂的鉴定提供信息，以促进这些和其他致命呼吸道感染的临床管理，并最终减轻人类的疾病负担。