Integrin ß4 is a receptor for emerging fungal pathogens from the genera Lomentospora and Scedosporium

Lomentospora prolificans is an environmental fungus that can cause life-threatening infections when airborne conidia are inhaled. Airway epithelial cells are likely to be the first host cells to interact with L. prolificans during pulmonary infection; however, the fungal and host factors that govern this interaction are completely unknown. Herein, we combined whole fungal cell pulldowns of surface proteins from airway epithelial cells and liquid chromatography-mass spectrometry (LC-MS) to identify host proteins that could potentially serve as host receptors for the fungus. We provide evidence that integrin β4 serves as a receptor that promotes the initial binding of L. prolificans to airway epithelial cells. Integrin β4 can associate with L. prolificans conidia that have been heat-killed or pre-treated with proteinase K suggesting that the fungal ligand is not proteinaceous. Inhibition of integrin β4 function by siRNA-mediated knockdown, or blocking with an anti-integrin β4 antibody, significantly inhibited the ability of L. prolificans to adhere to human airway epithelial cells. Integrin β4 can also associate with, and promote the adherence of, two closely related species of fungal pathogens, Scedosporium apiospermum and Scedosporium boydii. Overall, our study provides novel insight into the molecular mechanisms underlying the initiation of infection by L. prolificans, and two closely related species.