Division of Cell Biology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
PLoS Pathog. 2009 Dec;5(12):e1000697. doi: 10.1371/journal.ppat.1000697. Epub 2009 Dec 18.
Extraintestinal pathogenic E. coli (ExPEC) cause an array of diseases, including sepsis, neonatal meningitis, and urinary tract infections. Many putative virulence factors that might modulate ExPEC pathogenesis have been identified through sequencing efforts, epidemiology, and gene expression profiling, but few of these genes have been assigned clearly defined functional roles during infection. Using zebrafish embryos as surrogate hosts, we have developed a model system with the ability to resolve diverse virulence phenotypes and niche-specific restrictions among closely related ExPEC isolates during either localized or systemic infections. In side-by-side comparisons of prototypic ExPEC isolates, we observed an unexpectedly high degree of phenotypic diversity that is not readily apparent using more traditional animal hosts. In particular, the capacity of different ExPEC isolates to persist and multiply within the zebrafish host and cause disease was shown to be variably dependent upon two secreted toxins, alpha-hemolysin and cytotoxic necrotizing factor. Both of these toxins appear to function primarily in the neutralization of phagocytes, which are recruited in high numbers to sites of infection where they act as an essential host defense against ExPEC as well as less virulent E. coli strains. These results establish zebrafish as a valuable tool for the elucidation and functional analysis of both ExPEC virulence factors and host defense mechanisms.
肠外致病性大肠杆菌（ExPEC）可引起多种疾病，包括败血症、新生儿脑膜炎和尿路感染。通过测序、流行病学和基因表达谱分析，已经鉴定出许多可能调节 ExPEC 发病机制的潜在毒力因子，但这些基因中很少有明确的功能作用。我们利用斑马鱼胚胎作为替代宿主，开发了一种模型系统，该系统能够在局部或全身感染期间解析密切相关的 ExPEC 分离株之间的多种毒力表型和特定小生境的限制。在对原型 ExPEC 分离株的并排比较中，我们观察到一种出乎意料的高表型多样性，这在使用更传统的动物宿主时不容易察觉。特别是，不同 ExPEC 分离株在斑马鱼宿主内存活和繁殖并引起疾病的能力，被证明是可变的，这取决于两种分泌毒素，即α-溶血素和细胞毒性坏死因子。这两种毒素似乎主要作用于吞噬细胞的中和，吞噬细胞大量募集到感染部位，它们作为对抗 ExPEC 以及毒性较低的大肠杆菌菌株的重要宿主防御机制。这些结果确立了斑马鱼作为阐明 ExPEC 毒力因子和宿主防御机制的功能分析的有价值的工具。
