Oral Administration with Live Attenuated Citrobacter rodentium Protects Immunocompromised Mice from Lethal Infection

Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic E. coli (EHEC) are important causative agents for foodborne diseases worldwide. Besides antibiotic treatment, vaccination has been deemed as the most effective strategy for preventing EPEC- and EHEC-caused foodborne illnesses. Despite substantial progress made in identifying promising antigens and efficacious vaccines, no vaccines against EPEC or EHEC have yet been licensed. Mice are inherently resistant to EPEC and EHEC infections; infection with Citrobacter rodentium (CR), the murine equivalent of EPEC and EHEC, in mice has been widely used as a model to study bacterial pathogenesis and develop novel vaccine strategies. Mirroring the severe outcomes of EPEC and EHEC infections in immunocompromised populations, immunocompromised mouse strains such as interleukin-22 knockout (Il22) are susceptible to CR infection with severe clinical symptoms and mortality. Live attenuated bacterial vaccine strategies have been scarcely investigated for EPEC and EHEC infections, in particular in immunocompromised populations associated with severe outcomes. Here we examined whether live attenuated CR strain with rational genetic manipulation generates protective immunity against lethal CR infection in the susceptible Il22 mice. Our results demonstrate that oral administration of live ΔespFΔushA strain promotes efficient systemic and humoral immunity against a wide range of CR virulence determinants, thus protecting otherwise lethal CR infection, even in immunocompromised Il22 mice. This provides a proof of concept of live attenuated vaccination strategy for preventing CR infection in immunocompromised hosts associated with more severe symptoms and lethality.