Author:
P Dancer1, A Pickard2, W Potocka1, K Kadler2, M Bertuzzi1, S Gago1*
Author address:
1Manchester Fungal Infection Group, School of Biological Sciences. The University of Manchester, Manchester, UK
2Wellcome Centre for Cell-Matrix Research, School of Biological Sciences. The University of Manchester, Manchester, UK
Full conference title:
10th Advances Against Aspergillosis and Mucormycosis
Date: 2 February 2022
Abstract:
Purpose:
Aspergillus fumigatus is an ubiquitous fungus that cause pulmonary infections in immunocompromised patients or those with chronic lung diseases. The epidemiology of aspergillosis has recently changed and, patients with severe viral infection such as those with Covid-19 or influenza have an increased risk for the development of lethal forms of pulmonary aspergillosis. We have previously demonstrated that airway epithelial cells play a crucial role in host defence against A. fumigatus by directly internalising and killing internalised spores and by orchestrating further innate immune responses. Importantly, we also found that protective airway epithelial activities against fungal challenge are altered in patients susceptible to aspergillosis. Therefore, it is likely that a dysregulation of airway epithelial responses during fungal-viral coinfection represents a potent driver for aspergillosis.
Methods:
An in vitro model of A. fumigatus–viral coinfection of A549 alveolar epithelial cells was developed combining the use of fluorescently labelled A. fumigatus, FITC-Poly (I:C) and a nano-luciferase tagged version of SARS-CoV2. Coupling the use of imaging flow cytometry, fluorescent microscopy and a nano-luciferase activity assays, we quantitatively measured outcomes of spore internalisation, killing and viral replication during fungal-viral coinfection.
Results:
Uptake of A. fumigatus spores by airway epithelial cells was significantly increased in the presence of the viral mimic Poly(I:C). However, the ability of alveolar epithelial cells to kill internalised spores in the presence of viral stimulation was reduced therefore suggesting impaired airway antifungal responses during Aspergillus–viral coinfection. Additionally, type I viral-induced interferon release was abolished in the presence of A. fumigatus challenge suggesting a possible role of A. fumigatus in modulating antiviral responses. We next explored the impact of A. fumigatus challenge in SARS-CoV2 replication within airway epithelial cells using nano-luciferase as a measure of virus replication. Importantly, we found that Aspergillus–induced SARS-CoV2 replication was strain-dependent suggesting that some A. fumigatus strains might be better adapted to cause coinfection.
Conclusion:
Our findings demonstrate a mutual inhibition of antifungal and antiviral airway epithelial cell responses during Aspergillus–viral coinfection. We also found that some Aspergillus-specific fungal factors are critical regulators for viral pathogenicity. The experimental workflow that we
have developed will considerably improve our mechanistic understanding of the fungal and viral factors contributing to the pathophysiology of coinfection.
Abstract Number: 80
Conference Year: 2022
Link to conference website: https://aaam2022.org/
URL Conference abstract: