EGF-mediated suppression of cell extrusion during mucosal damage attenuates opportunistic fungal invasion

Severe and often fatal opportunistic fungal infections arise frequently following mucosal damage caused by trauma or cytotoxic chemotherapy. Interaction of fungal pathogens with epithelial cells that comprise mucosae 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 promotes exposure of laminin associated with increased fungal attachment, invasion, and larval lethality, whereas fungi defective in adherence or filamentation have reduced virulence. Transcriptional profiling identifies significant upregulation of the epidermal growth factor receptor ligand epigen (EPGN) upon mucosal damage. Treatment with recombinant human EPGN suppresses epithelial cell extrusion, leading to reduced fungal invasion and significantly enhanced survival. These data support the concept of augmenting epithelial restorative capacity to attenuate pathogenic invasion of fungi associated with human disease. [Display omitted] •Inducible epithelial cell loss allows modeling of fungal infection in zebrafish larvae•Extrusion of numerous cells exposes laminin and increases fungal adhesion and invasion•Cell extrusion stimulates epigen, mmp13a, and il1b expression and neutrophil recruitment•rhEPGN suppresses extrusion to provide protective effects against fungal invasion Wurster et al. show that extrusion of numerous epithelial cells from tissue can expose underlying extracellular matrix components to promote increased attachment and invasion of fungi associated with human disease. Treatment with recombinant human EPGN suppressed epithelial cell extrusion, leading to significantly reduced opportunistic fungal invasion.