Lung colonization by Aspergillus fumigatus is controlled by ZNF77

Sara Gago, Nicola L. D. Overton, Nagwa Ben-Ghazzi, Lilyann Novak-Frazer, Nick D. Read, David W. Denning and Paul Bowyer ()
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Sara Gago: University of Manchester
Nicola L. D. Overton: University of Manchester
Nagwa Ben-Ghazzi: University of Manchester
Lilyann Novak-Frazer: The University of Manchester and University Hospital of South Manchester NHS Foundation Trust
Nick D. Read: University of Manchester
David W. Denning: University Hospital of South Manchester NHS Foundation Trust
Paul Bowyer: University of Manchester

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Aspergillus fumigatus is a critical pathogen of humans. Exposure to A. fumigatus conidia occurs frequently but is normally cleared from the respiratory airways. In contrast, individuals with respiratory diseases are often highly colonized by fungi. Here, we use genome-edited epithelial cells to show that the genetic variant rs35699176 in ZNF77 causes loss of integrity of the bronchial epithelium and increases levels of extracellular matrix proteins. These changes promote A. fumigatus conidial adhesion, germination and growth. RNA-seq and LC/MS-MS analysis reveal rs35699176 upregulates vesicle trafficking leading to an increment of adhesion proteins. These changes make cells carrying rs35699176 more receptive to A. fumigatus in the early stages of infection. Moreover, patients with fungal asthma carrying rs35699176+/− have higher A. fumigatus loads in their respiratory airway. Our results indicate ZNF77 as a key controller of Aspergillus colonization and suggest its utility as a risk-marker for patient stratification.

Date: 2018
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DOI: 10.1038/s41467-018-06148-7

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