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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.

SUBMITTER: Wurster S

PROVIDER: S-EPMC8842569 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Wurster Sebastian S Ruiz Oscar E OE Samms Krystin M KM Tatara Alexander M AM Albert Nathaniel D ND Kahan Philip H PH Nguyen Anh Trinh AT Mikos Antonios G AG Kontoyiannis Dimitrios P DP Eisenhoffer George T GT

Cell reports 20210301 12

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 pro ...[more]

PMID: 33761358

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Project description:BackgroundRemote ischemic preconditioning (RIPC) is a phenomenon, whereby repeated, non-lethal episodes of ischemia to an organ or limb exert protection against ischemia-reperfusion (I/R) injury in distant organs. Despite intensive research, there is still an apparent lack of knowledge concerning the RIPC-mediated mechanisms, especially in the intestine. Aim of this study was to evaluate possible protective effects RIPC on intestinal I/R injury.MethodsThirty rats were randomly assigned to four groups: I/R; I/R + RIPC; Sham; Sham + RIPC. Animals were anesthetized and the superior mesenteric artery was clamped for 30 min, followed by 60 min of reperfusion. RIPC-treated rats received 3 × 5 min of bilateral hindlimb I/R prior to surgery, sham groups obtained laparotomy without clamping. After I/R injury serum/tissue was analyzed for: Mucosal damage, Caspase-3/7 activity, expression of cell stress proteins, hydrogen peroxide (H2O2) and malondialdehyde (MDA) production, Hypoxia-inducible factor-1α (HIF-1α) protein expression and matrix metalloproteinase (MMP) activity.ResultsIntestinal I/R resulted in increased mucosal injury (P < 0.001) and elevated Caspase-3/7 activity (P < 0.001). RIPC significantly reduced the histological signs of intestinal I/R injury (P < 0.01), but did not affect Caspase-3/7 activity. Proteome profiling suggested a RIPC-mediated regulation of several cell stress proteins after I/R injury: Cytochrome C (+ 157%); Cited-2 (- 39%), ADAMTS1 (+ 74%). Serum concentrations of H2O2 and MDA remained unchanged after RIPC, while the reduced intestinal injury was associated with increased HIF-1α levels. Measurements of MMP activities in serum and intestinal tissue revealed an attenuated gelatinase activity at 130 kDa within the serum samples (P < 0.001) after RIPC, while the activity of MMPs within the intestinal tissue was not affected by I/R injury or RIPC.ConclusionsRIPC ameliorates intestinal I/R injury in rats. The underlying mechanisms may involve HIF-1α protein expression and a decreased serum activity of a 130 kDa factor with gelatinase activity.

Dataset Information

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

Publications

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

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