EGF-Mediated Suppression of Cell Extrusion During Mucosal Damage Attenuates Opportunistic Fungal Invasion

Abstract

Severe, often fatal, opportunistic fungal infections frequently arise following mucosal damage caused by trauma or cytotoxic chemotherapy. Interaction of fungal pathogens with epithelial cells that comprise mucosa is a key early event associated with invasion, and therefore, enhancing epithelial defense mechanisms may mitigate infection. Here we establish a model of mold and yeast infection mediated by inducible epithelial cell loss in larval zebrafish. Epithelial cell loss by extrusion promoted exposure of laminin that was associated with increased fungal attachment, invasion and larval lethality, while fungi defective in adherence or filamentation did not impact survival. Transcriptional profiling identified significant upregulation of the epidermal growth factor receptor ligand epigen (EPGN) upon mucosal damage. Treatment with recombinant human EPGN suppressed epithelial cell extrusion, leading to reduced fungal invasion and significantly enhanced survival. Together, these data support the concept of augmenting epithelial restorative capacity to attenuate pathogenic invasion of fungi associated with human disease.