Abstract
Hemolytic uremic syndrome (HUS), principally caused by shiga toxins (Stxs), is associated with Shiga toxin-producing Escherichia coli (STEC) infections. We previously reported Stx2 expression by host cells in vitro and in vivo. As the genes encoding the two Stx subunits are located in bacteriophage genomes, the aim of the current study was to evaluate the role of bacteriophage induction in HUS development in absence of an E. coli O157:H7 genomic background. Mice were inoculated with a non-pathogenic E. coli strain carrying the lysogenic bacteriophage 933W (C600Φ933W), and bacteriophage excision was induced by an antibiotic. The mice died 72 h after inoculation, having developed pathogenic damage typical of STEC infection. As well as renal and intestinal damage, markers of central nervous system (CNS) injury were observed, including aberrant immunolocalization of neuronal nuclei (NeuN) and increased expression of glial fibrillary acidic protein (GFAP). These results show that bacteriophage 933W without an E. coli O157:H7 background is capable of inducing the pathogenic damage associated with STEC infection. In addition, a novel mouse model was developed to evaluate therapeutic approaches focused on the bacteriophage as a new target.
Highlights
During infection with Shiga toxin-producing E. coli (STEC), which harbors the temperate bacteriophage 933W (Plunkett et al, 1999), phages undergo excision and replication and Shiga toxin (Stx) is expressed and released
Mice infected intragastrically with 2 × 107 CFU/mouse nonpathogenic C600 strain lysogenized with bacteriophage 933W (C600 933W) died 72 h post-infection (Figure 1B)
Shiga toxin-producing E. coli has long been recognized as a principal cause of Hemolytic uremic syndrome (HUS) (Richardson et al, 1988; Karmali, 1989)
Summary
During infection with Shiga toxin-producing E. coli (STEC), which harbors the temperate bacteriophage 933W (Plunkett et al, 1999), phages undergo excision and replication and Shiga toxin (Stx) is expressed and released. The free bacteriophages are able to infect other susceptible bacteria in the gut, exacerbating bacteriophage replication and Stx production (Muniesa and Schmidt, 2014). Bacteriophage excision is linked to the SOS response of bacteria (Kimmitt et al, 2000). Several antibiotics, such as mitomycin C and quinolones, including ciprofloxacin, are contraindicated in STEC infections, because at antimicrobial levels above those required to inhibit bacterial replication they cause DNA damage. Relevance of Bacteriophage 933W in HUS Development effect of simultaneously triggering phage production and expression of stx genes. It has been reported that an STEC strain mutated in the cleavage mechanism was unable to induce renal disease and lethality in a mouse model (Tyler et al, 2013)
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