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Confocal Laser Scanning Microscopy-Based Quantitative Analysis of Aspergillus fumigatus Conidia Distribution in Whole-Mount Optically Cleared Mouse Lung
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Lung colonization by Aspergillus fumigatus is controlled by ZNF77

Sara Gago1, Nicola L D Overton1,2, Nagwa Ben-Ghazzi1

  • 1Manchester Fungal Infection Group, Division of Infection, Immunity and Respiratory Medicine, University of Manchester, CTF Building, 46 Grafton Street, Manchester, M13 9NT, UK.

Nature Communications
|September 22, 2018
PubMed

Insights

A genetic variant in ZNF77 (rs35699176) disrupts bronchial epithelium integrity, promoting Aspergillus fumigatus colonization. This finding offers a potential biomarker for identifying patients at higher risk of fungal asthma.

Area of Science:

  • Medical Mycology
  • Human Genetics
  • Respiratory Medicine

Background:

  • Aspergillus fumigatus is a significant human pathogen.
  • Respiratory diseases increase susceptibility to fungal colonization.
  • The role of specific genetic variants in A. fumigatus susceptibility is not fully understood.

Purpose of the Study:

  • To investigate the impact of the genetic variant rs35699176 in ZNF77 on bronchial epithelial integrity and A. fumigatus interaction.
  • To elucidate the molecular mechanisms underlying ZNF77 variant-mediated susceptibility.
  • To assess the clinical relevance of ZNF77 in patients with fungal asthma.

Main Methods:

  • Genome-edited human bronchial epithelial cells.
  • RNA-sequencing (RNA-seq).
  • Liquid chromatography-tandem mass spectrometry (LC/MS-MS).
  • Analysis of patient samples from fungal asthma cohorts.

Main Results:

  • The ZNF77 variant rs35699176 impairs bronchial epithelial integrity and increases extracellular matrix proteins.
  • This variant upregulates vesicle trafficking and adhesion proteins, enhancing A. fumigatus conidial adhesion, germination, and growth.
  • Patients with fungal asthma carrying rs35699176 exhibit higher A. fumigatus loads.

Conclusions:

  • ZNF77 is a key regulator of Aspergillus colonization in the respiratory tract.
  • The rs35699176 variant in ZNF77 represents a risk factor for increased fungal burden.
  • ZNF77 may serve as a valuable biomarker for stratifying patients with fungal respiratory infections.

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