Dataset Information

Lung colonization by Aspergillus fumigatus is controlled by ZNF77.

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.

SUBMITTER: Gago S

PROVIDER: S-EPMC6147781 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Lung colonization by Aspergillus fumigatus is controlled by ZNF77.

Gago Sara S Overton Nicola L D NLD Ben-Ghazzi Nagwa N Novak-Frazer Lilyann L Read Nick D ND Denning David W DW Bowyer Paul P

Nature communications 20180920 1

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 ad ...[more]

PMID: 30237437

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Project description:Germination from conidia to hyphae and hyphal propagation of Aspergillus fumigatus are the key pathogenic steps in the development of invasive pulmonary aspergillosis (IPA). By applying in vitro observations in a clinical study of 13 patients diagnosed with probable IPA, here, we show that the transition from colonization to the A. fumigatus invasive stage is accompanied by the secretion of triacetylfusarinine C (TafC), triacetylfusarinine B (TafB), and ferricrocin (Fc) siderophores into urine, with strikingly better sensitivity performance than serum sampling. The best-performing index, the TafC/creatinine index, with a median value of 17.2, provided 92.3% detection sensitivity (95% confidence interval [CI], 64.0 to 99.8%) and 100% specificity (95% CI, 84.6 to 100%), i.e., substantially better than the corresponding indications provided by galactomannan (GM) and β-d-glucan (BDG) serology. For the same patient cohort, the serum GM and BDG sensitivities were 46.2 and 76.9%, respectively, and their specificities were 86.4 and 63.6%, respectively. The time-dependent specific appearance of siderophores in the host's urine represents an impactful clinical diagnostic advantage in the early discrimination of invasive aspergillosis from colonization. A favorable concentration of TafC in a clinical specimen distant from a deep infection site enables the noninvasive sampling of patients suffering from IPA. IMPORTANCE The importance of this research lies in the demonstration that siderophore analysis can distinguish between asymptomatic colonization and invasive pulmonary aspergillosis. We found clear associations between phases of fungal development, from conidial germination to the proliferative stage of invasive aspergillosis, and changes in secondary metabolite secretion. The critical extracellular fungal metabolites triacetylfusarinines C and B are produced during the polarized germination or postpolarized growth phase and reflect the morphological status of the proliferating pathogen. False positivity in Aspergillus diagnostics is minimized as mammalian cells do not synthesize Aspergillus siderophore or mycotoxin molecules.

Dataset Information

Lung colonization by Aspergillus fumigatus is controlled by ZNF77.

Publications

Lung colonization by Aspergillus fumigatus is controlled by ZNF77.

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