EGF-mediated suppression of cell extrusion during mucosal damage attenuates opportunistic fungal invasion
Sebastian Wurster,
Oscar E. Ruiz,
Krystin M. Samms,
Alexander M. Tatara,
Nathaniel D. Albert,
Philip H. Kahan,
Anh Trinh Nguyen,
Antonios G. Mikos,
Dimitrios P. Kontoyiannis,
George T. Eisenhoffer
Affiliations
Sebastian Wurster
Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Oscar E. Ruiz
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Krystin M. Samms
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Alexander M. Tatara
Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA
Nathaniel D. Albert
Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Philip H. Kahan
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Anh Trinh Nguyen
Department of Microbiology and Molecular Genetics, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA; MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
Antonios G. Mikos
Department of Bioengineering, Rice University, Houston, TX, USA
Dimitrios P. Kontoyiannis
Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Corresponding author
George T. Eisenhoffer
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA; Corresponding author
Summary: 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.
