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Proteomic characterization of Aspergillus fumigatus - host interactions using the ex-vivo pig lung (EVPL) model
Aaron Curtis1, Freya Harrison2, Kevin Kavanagh1
1Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.
Abstract:
Aspergillus fumigatus is an opportunistic fungal pathogen of the human airway that can cause a variety of chronic infections, typically in the context of pre-existing lung damage. The interaction of A. fumigatus with ex-vivo pig lung (EVPL) samples was characterized at the proteomic level to provide insights into how the fungus may interact with pulmonary tissue in vivo. This model has many advantages, because pigs share 90% immunological homology with humans and display many anatomical similarities. EVPL also retains resident immune cells, has richer cellular complexity compared to in-vitro models, and has a microbiome. Label-free quantitative proteomic analysis identified the metabolism and development of A. fumigatus on the EVPL alveolar sections; at 48 h, there was an increased abundance of proteins associated with carbon metabolism (e.g. malate dehydrogenase (+8.2 fold increase)), and amino acid metabolism and biosynthesis (e.g. 5-methyltetrahydropteroyltriglutamate - homocysteine S-methyltransferase, (+5.04 fold)) at 72 h. Porcine tissue remained responsive to the pathogen with proteins that increased in abundance associated with innate immune recruitment (e.g. protein S100-A8 (+28.5 fold) and protein S100-A9 (calgranulin-B) (+7.25 fold)) at 24 h, while proteins associated with neutrophil degranulation (e.g. elastase, neutrophil (-2.74 fold)) decreased in abundance. At 96 h, the infected tissue demonstrated enhanced abundance of fibrotic markers (e.g. fibrillin 1, collagen type IV alpha 1 chain, and alpha 2 chain, increased by + 16.44, +15.42 and + 11.95 fold, respectively). These results validate the use of this model for studying pathogen-host interactions and highlight how A. fumigatus interacts with pulmonary tissue during colonization.
Insights
This study used ex-vivo pig lung models to analyze Aspergillus fumigatus interactions. The proteomic analysis revealed fungal metabolism changes and host immune and fibrotic responses in the lung tissue.
Area of Science:
- Mycology and Immunology
- Proteomics and Pathogen-Host Interactions
Background:
- Aspergillus fumigatus is an opportunistic fungal pathogen causing chronic airway infections, often in individuals with pre-existing lung damage.
- Understanding fungal-host interactions in the pulmonary system is crucial for developing effective treatments.
- Existing in vitro models lack the complexity of the in vivo lung environment.
Purpose of the Study:
- To characterize the proteomic interactions between Aspergillus fumigatus and ex-vivo pig lung (EVPL) tissue.
- To gain insights into fungal behavior and host responses during pulmonary colonization using a relevant animal model.
- To validate the EVPL model for studying pathogen-host dynamics in the airway.
Main Methods:
- Label-free quantitative proteomic analysis was performed on EVPL samples infected with Aspergillus fumigatus at various time points (24h, 48h, 72h, 96h).
- The EVPL model was chosen due to anatomical and immunological similarities to human lungs, retaining resident immune cells and a microbiome.
- Proteomic data was analyzed to identify changes in fungal metabolism and host tissue responses.
Main Results:
- Proteomic analysis revealed increased abundance of fungal proteins related to carbon and amino acid metabolism at 48-72 hours post-infection.
- Host tissue showed an upregulation of innate immune recruitment proteins (e.g., S100-A8, S100-A9) at 24 hours, with a decrease in neutrophil degranulation markers.
- Significant increases in fibrotic markers (e.g., fibrillin 1, collagen type IV) were observed by 96 hours, indicating tissue remodeling.
Conclusions:
- The ex-vivo pig lung model effectively mimics human pulmonary responses to Aspergillus fumigatus infection.
- The study highlights dynamic changes in fungal metabolism and host immune and fibrotic responses during colonization.
- These findings support the utility of the EVPL model for investigating fungal pathogenesis and host-pathogen interactions in the lung.
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