Lung colonization by Aspergillus fumigatus is controlled by ZNF77.

TitleLung colonization by Aspergillus fumigatus is controlled by ZNF77.
Publication TypeJournal Article
Year of Publication2018
AuthorsGago, S, Overton, NLD, Ben-Ghazzi, N, Novak-Frazer, L, Read, ND, Denning, DW, Bowyer, P
JournalNat Commun
Volume9
Issue1
Pagination3835
Date Published2018 Sep 20
ISSN2041-1723
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.

DOI10.1038/s41467-018-06148-7
Alternate JournalNat Commun
PubMed ID30237437
Grant ListMR/M02010X/1 / / Medical Research Council (MRC) /
NC/P002390/1 / / National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) /