Mechanistic basis of the antifungal potency of the airway epithelium in health and disease

Author:

Margherita Bertuzzi (UK)

Abstract:

Background: The fungal pathogen Aspergillus fumigatus (Af) affects >3,000,000 individuals annually, with invasive aspergillosis having mortality rates of >50%. Airway Epithelial Cells (AECs), which cover the entire alveolar surface and comprise 24% of all cells in the human lung parenchyma, have immediate, extensive, and likely prolonged contact with Af conidia upon inhalation. We previously demonstrated that AECs provide a potent means of antifungal defense against Af in vivo, and that dysfunctional epithelial antifungal activity in at-risk patients may provide an opportunity for Af to exploit AECs as a safe haven to reside intracellularly. However, the fungal and host factors controlling Af uptake and clearance by AECs are poorly understood.

Methods: To determine how healthy AECs recognise and kill Af and how these processes are dysregulated in disease, we exploit single-cell workflows to perform molecular, transcriptional, and cellular analyses of the Af-AEC interaction in vitro and in vivo.

Results: Using fluorescent auxotrophic pyrG- strains locked at specific morphological stages, we determined morphotype-specific interactions with AECs, whereby swollen conidia locked at 3 and 6 hours of germination are 2-fold more readily internalized than conidia locked at 0 hours. Probing with fluorescent lectins, we identified mannose as a key surface carbohydrate that show a morphotype-specific increase during germination. Supporting this, mannose and the mannose- binding lectin Concanavalin A were able to respectively reduce (by 88%) and abolish (100%) Af internalization. Using a combination of Af mutants, and AEC receptor mutants, we are systematically evaluating morphotype-specific factors on Af surface and characterizing key host receptors for their role in mediating fungal uptake and clearance both healthy and diseased AECs.

Conclusions: Understanding how AECs contribute to antifungal clearance by recognizing morphotype-specific fungal factors is of mayor clinical importance as it could inform the development of much needed novel antifungal therapeutics.

Abstract Number: 58

Conference Year: 2024

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