Oral Vaccination with Live Attenuated Pathogenic Bacteria Protects Immunocompromised Hosts from Lethal Colitis

Enteropathogenic Escherichia coli(EPEC) and enterohemorrhagic E. coli(EHEC) are significant causative agents for diarrheal diseases globally. Vaccination has been deemed as the most effective strategy for preventing EPEC and EHEC caused foodborne illnesses; however, FDA has not yet licensed any vaccine against EPEC or EHEC. Of note, live attenuated bacterial vaccine strategy has been scarcely investigated for against EPEC or EHEC infection, in particular in immunocompromised populations where the infections are associated with severe symptoms and outcomes. Infection with Citrobacter rodentium(CR), the murine equivalent of EPEC and EHEC, in mice has been widely used to develop novel vaccine strategies and evaluate vaccination efficacy. CR infection in immunocompromised mice such as interleukin-22 knockout (Il22−/−) mice leads to severe symptoms and mortality, which mirrors the severe outcomes of EPEC and EHEC infections in immunocompromised populations. We explored whether oral inoculation with live CR mutants with rationally attenuated virulence could protect lethal infection in susceptible Il22−/−mice. We showed that oral administration of live attenuated CR strains elicited efficient systemic and humoral immunity against variant CR virulence proteins, hence protecting otherwise lethal CR infection, in Il22−/−mice. Our findings provide proof of concept evidence for live attenuated vaccination strategy to prevent EPEC/EHEC infections in immunocompromised hosts associated with more severe symptoms and lethality, and reveal novel CR-specific antibody subtypes and virulence determinants that are critical for live attenuated vaccination offered immune protection.