title: Use of zebrafish to probe the divergent virulence potentials and toxin requirements of extraintestinal pathogenic Escherichia coli.
abstract: 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.
authors.affiliation: Division of Cell Biology and Immunology, Department of Pathology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Travis J
authors.initials: TJ
authors.lastname: Wiles
authors.forename: Jean M
authors.initials: JM
authors.lastname: Bower
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Redd
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Mulvey
mesh_terms: D000818:Animals; D001427:Bacterial Toxins; D004625:Embryo, Nonmammalian; D004926:Escherichia coli / Q000472:pathogenicity*; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; D054884:Host-Pathogen Interactions; D010641:Phenotype; D014774:Virulence; D015027:Zebrafish
chemical_list: D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; C036507:Hlya protein, E coli; C060296:cytotoxic necrotizing factor type 1