Impact of Anti-Shiga Toxin Type 2 (Stx2) Neutralizing Antibody on Colonization and Pathogenesis of Escherichia Coli O157:H7 in Mice

Escherichia coli O157H7 was first clearly documented as a human pathogen when it caused an outbreak of hamburger associated bloody diarrhea, or hemorrhagic colitis HC in 1982. In the ensuing years, E. coli O157H7 has been responsible for multiple food- and water-borne outbreaks of diarrhea andor HC worldwide. A portion 4-15 of such E. coli O157H7-infected individuals develop a life-threatening sequela of infection called hemolytic uremic syndrome or HUS. The major virulence factor that has been linked to both the presentation of HC and HUS is Shiga toxin Stx, a potent cytotoxin that can cause inhibition of protein synthesis in sensitive target cells such as in the kidneys. The goal of this research was to help elucidate the course of E. coli O157H7 pathogenesis to facilitate treatment and prevention of disease. For that purpose, we first developed a conventional mouse model in which the E. coli O157H7 introduced by pipette feeding or gavage had to compete with the resident microbiota to establish infection. This intact commensal flora ICF adult mouse model is one of the few such murine models described to date that permits the evaluation of both colonization by E. coli O157H7 and the subsequent systemic disease associated with Stx production. Through the use of this ICF model, we next went on to demonstrate not only a role for Stx in E. coli O157H7 colonization, but more importantly, a role for anti-Stx antibody in reducing colonization. Our results suggest that a vaccine to reduce E. coli O157H7 disease should include a toxoid component not only because anti-toxin antibodies would prevent Stx toxicity but also because anti-toxin antibodies may reduce bacterial colonization. Thus, we propose that our animal model and findings on colonization by E. coli O157H7 and the subsequent impact of Stx produced in the gut may further advance the development and use of toxoid-based vaccines and therapeutic strategies against E. coli O157H7.