@article{68ef3c27140c4e70a74b062581a7c52d,
title = "EGF-mediated suppression of cell extrusion during mucosal damage attenuates opportunistic fungal invasion",
abstract = "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.",
keywords = "EGF signaling, cell extrusion, epitheli, fungi, zebrafish",
author = "Sebastian Wurster and Ruiz, {Oscar E.} and Samms, {Krystin M.} and Tatara, {Alexander M.} and Albert, {Nathaniel D.} and Kahan, {Philip H.} and Nguyen, {Anh Trinh} and Mikos, {Antonios G.} and Kontoyiannis, {Dimitrios P.} and Eisenhoffer, {George T.}",
note = "Funding Information: This work was supported by the Cancer Prevention Institute of Texas ( RR14007 ), the National Institute of General Medical Sciences ( GM124043 ), and the Linda and Mark Quick Award for Basic Science (to G.T.E.) and in part by a Cancer Center support grant ( P30CA016672 ), the Texas 4000 distinguished professorship endowment, and the Robert C. Hickey Chair in Clinical Care endowment (to D.P.K.). We thank Kenneth Dunner, Jr. at the UT MD Anderson High Resolution Electron Microscopy Facility for assistance with electron microscopy data and Jordan Pietz at the Creative Communications group at MD Anderson Cancer Center for biomedical visualization. The High Resolution Electron Microscopy and Flow Cytometry and Cellular Imaging core facilities were supported by CCSG grant NIH P30CA016672 . The Sequencing and Microarray facility was supported by a National Cancer Institute grant ( CA016672) . Funding Information: This work was supported by the Cancer Prevention Institute of Texas (RR14007), the National Institute of General Medical Sciences (GM124043), and the Linda and Mark Quick Award for Basic Science (to G.T.E.) and in part by a Cancer Center support grant (P30CA016672), the Texas 4000 distinguished professorship endowment, and the Robert C. Hickey Chair in Clinical Care endowment (to D.P.K.). We thank Kenneth Dunner, Jr. at the UT MD Anderson High Resolution Electron Microscopy Facility for assistance with electron microscopy data and Jordan Pietz at the Creative Communications group at MD Anderson Cancer Center for biomedical visualization. The High Resolution Electron Microscopy and Flow Cytometry and Cellular Imaging core facilities were supported by CCSG grant NIH P30CA016672. The Sequencing and Microarray facility was supported by a National Cancer Institute grant (CA016672). D.P.K. and G.T.E. conceived of the study. S.W. and O.E.R. performed all experiments and subsequent analyses. A.M.T. optimized the fungal infection assay. K.M.S. performed imaging and cell tracking analyses. A.T.N. assisted with live imaging of the fungal/neutrophil interface. P.H.K. and N.D.A. provided key technical support. A.G.M. helped to develop the initial fungal infection platform. S.W. O.E.R. D.P.K. and G.T.E. wrote the manuscript. D.P.K. reports research support from Astellas Pharma and honoraria for lectures or consultantships from Merck & Co. Astellas Pharma, Gilead Sciences, Mayne Pharmaceuticals, Amplyx Pharmaceuticals, and Pulmocide, Inc. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = mar,
day = "23",
doi = "10.1016/j.celrep.2021.108896",
language = "English (US)",
volume = "34",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "12",
}