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

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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.