Department of Molecular and Biomedical Sciences, University of Maine, Orono, ME 04469, USA.
Dis Model Mech. 2013 Sep;6(5):1260-70. doi: 10.1242/dmm.012039. Epub 2013 May 29.
The epithelium performs a balancing act at the interface between an animal and its environment to enable both pathogen killing and tolerance of commensal microorganisms. Candida albicans is a clinically important human commensal that colonizes all human mucosal surfaces, yet is largely prevented from causing mucosal infections in immunocompetent individuals. Despite the importance of understanding host-pathogen interactions at the epithelium, no immunocompetent vertebrate model has been used to visualize these dynamics non-invasively. Here we demonstrate important similarities between swimbladder candidiasis in the transparent zebrafish and mucosal infection at the mammalian epithelium. Specifically, in the zebrafish swimmbladder infection model, we show dimorphic fungal growth, both localized and tissue-wide epithelial NF-κB activation, induction of NF-κB -dependent proinflammatory genes, and strong neutrophilia. Consistent with density-dependence models of host response based primarily on tissue culture experiments, we show that only high-level infection provokes widespread activation of NF-κB in epithelial cells and induction of proinflammatory genes. Similar to what has been found using in vitro mammalian models, we find that epithelial NF-κB activation can occur at a distance from the immediate site of contact with epithelial cells. Taking advantage of the ability to non-invasively image infection and host signaling at high resolution, we also report that epithelial NF-κB activation is diminished when phagocytes control the infection. This is the first system to model host response to mucosal infection in the juvenile zebrafish, and offers unique opportunities to investigate the tripartite interactions of C. albicans, epithelium and immune cells in an intact host.
上皮细胞在动物与其环境的界面上发挥着平衡作用，既能杀死病原体，又能耐受共生微生物。白色念珠菌是一种重要的临床共生人类微生物，定植于所有人类黏膜表面，但在免疫功能正常的个体中，其很大程度上被阻止引起黏膜感染。尽管了解上皮细胞的宿主-病原体相互作用非常重要，但还没有免疫功能正常的脊椎动物模型被用于非侵入性地可视化这些动态。在这里，我们展示了透明斑马鱼气囊念珠菌病和哺乳动物上皮黏膜感染之间的重要相似性。具体来说，在斑马鱼气囊感染模型中，我们观察到真菌形态的二态性生长，局部和全组织上皮 NF-κB 激活，NF-κB 依赖性促炎基因的诱导，以及强烈的中性粒细胞增多。与主要基于组织培养实验的宿主反应密度依赖性模型一致，我们表明只有高水平感染才能引发上皮细胞中 NF-κB 的广泛激活和促炎基因的诱导。与使用体外哺乳动物模型所发现的情况相似，我们发现上皮 NF-κB 激活可以发生在与上皮细胞直接接触的部位之外。利用非侵入性高分辨率成像感染和宿主信号的能力，我们还报告称，当吞噬细胞控制感染时，上皮 NF-κB 激活会减弱。这是第一个在幼年斑马鱼中模拟黏膜感染宿主反应的系统，为研究白色念珠菌、上皮细胞和免疫细胞在完整宿主中的三方相互作用提供了独特的机会。
