Novel Host Pathways Govern Epithelial Cell Invasion of Aspergillus fumigatus.

Invasive aspergillosis is initiated when Aspergillus fumigatus adheres to and invades the pulmonary epithelial cells that line the airways and alveoli. To gain deeper insight into how pulmonary epithelial cells respond to A. fumigatus invasion, we used transcriptome sequencing (RNA-seq) to determine the transcriptional response of the A549 type II alveolar epithelial cell line to infection with strains CEA10 and Af293, two clinical isolates of A. fumigatus. Upstream regulator analysis of the data indicated that while both strains activated virtually identical host cell signaling pathways after 16 h of infection, only strain CEA10 activated these pathways after 6 h of infection. Many of the pathways that were predicted to be activated by A. fumigatus, including the tumor necrosis factor (TNF), interleukin-1α (IL-1α), IL-1β, IL-17A, Toll-like receptor 2 (TLR2), and TLR4 pathways, are known to be critical for the host defense against this fungus. We also found that the platelet-derived growth factor BB (PDGF BB) and progesterone receptor (PGR) pathways were activated by A. fumigatus. Using pharmacologic inhibitors, we determined that blocking the PDGF receptor or PGR inhibited the endocytosis of both strains of A. fumigatus in an additive manner. Both the PDGF BB and PGR pathways are also predicted to be activated by infection of A549 cells with other molds, such as Rhizopus delemar and Rhizopus oryzae. Thus, these pathways may represent a common response of pulmonary epithelial cells to mold infection.