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Profiling the early molecular response of the human bronchial epithelium to Aspergillus fumigatus using a multi-omics approach Toor, Amreen


Aspergillus fumigatus (A. fumigatus) is an opportunistic fungal pathogen that is widely distributed in nature through the release of conidiospores (conidia). Upon inhalation, fungal conidia (2-3 μm) are capable of reaching the bronchial and alveolar epithelia. This interaction between conidia and airway epithelial cells may result in the development of allergic, chronic or invasive aspergillosis in susceptible hosts. Characterization of the early molecular response of host using a multi-OMICs molecular approach is an important first step for better understanding the host-pathogen interaction. The aim of my research was to investigate the early molecular response of host upon interaction with A. fumigatus using an in-vitro model that closely recapitulates the in-vivo bronchial epithelium, and assess the applicability of this model to study host-pathogen interactions. A multi-OMICs approach utilizing NanoString and shotgun proteomics was applied to primary human bronchial epithelial cells (HBECs) grown for 21-28 days as differentiated air-liquid interface (ALI) cultures. Comparative analyses were conducted to compare the gene expression profiles of ALI cultures to submerged monolayer cultures of human airway epithelial cell line (1HAEo-) upon conidial exposure. In addition, transcriptional profiles of ALI cultures upon exposure to wild-type (WT) conidia of A. fumigatus were compared to Kdnase mutant strain (Δkdnase) of A. fumigatus and to Respiratory Syncytial Virus (RSV). Unlike submerged monolayer cultures, ALI cultures of primary HBECs internalized less than 1% of bound conidia 6 hours post-exposure. Transcriptomic and proteomic analyses of primary HBECs in ALI revealed that exposure to the fungus enriched the expression of genes related to cell cycle regulation, apoptosis/autophagy, iron homeostasis, calcium metabolism, complement and coagulation cascades, endoplasmic stress and the unfolded protein response. Comparative analyses to submerged monolayer cultures of 1HAEs indicated that the host molecular response in each model is different. The immune response in differentiated ALI cultures upon exposure to Δkdnase A. fumigatus conidia and RSV was pathogen-specific. Hence, ALI cultures of primary HBECs can provide novel insights into the mechanisms involved in the early molecular response associated with this opportunistic fungal pathogen.

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