Wurster Sebastian, Ruiz Oscar E, Samms Krystin M, Tatara Alexander M, Albert Nathaniel D, Kahan Philip H, Nguyen Anh Trinh, Mikos Antonios G, Kontoyiannis Dimitrios P, Eisenhoffer George T
Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Cell Rep. 2021 Mar 23;34(12):108896. doi: 10.1016/j.celrep.2021.108896.
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.
创伤或细胞毒性化疗引起的粘膜损伤后，严重且往往致命的机会性真菌感染频繁发生。真菌病原体与构成粘膜的上皮细胞之间的相互作用是与侵袭相关的关键早期事件，因此，增强上皮防御机制可能减轻感染。在这里，我们建立了一个由幼虫斑马鱼中诱导性上皮细胞丢失介导的霉菌和酵母菌感染模型。通过挤压导致的上皮细胞丢失促进了与真菌附着、侵袭和幼虫致死率增加相关的层粘连蛋白暴露，而在粘附或丝状化方面存在缺陷的真菌毒力降低。转录谱分析确定了粘膜损伤后表皮生长因子受体配体Epigen（EPGN）的显著上调。用重组人EPGN治疗可抑制上皮细胞挤压，导致真菌侵袭减少并显著提高存活率。这些数据支持增强上皮修复能力以减弱与人类疾病相关的真菌致病性侵袭这一概念。
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