Intimin-specific immune responses prevent bacterial colonization by the attaching-effacing pathogen Citrobacter rodentium

The formation of attaching and effacing (A/E) lesions on gut enterocytes is central to the pathogenesis of enterohemorrhagic (EHEC) Escherichia coli, enteropathogenic E. coli (EPEC), and the rodent pathogen Citrobacter rodent ium. Genes encoding A/E lesion formation map to a chromosomal pathogenicity island termed the locus of enterocyte effacement (LEE). Here we show that the LEE-encoded proteins EspA, EspB, Tir, and intimin are the targets of lo ng-lived humoral immune responses in C. rodentium-infected mice. Mice infec ted with C. rodentium developed robust acquired immunity and were resistant to reinfection with wild-type C. rodentium or a C. rodentium derivative, D BS255(pCVD438), which expressed intimin derived from EPEC strain E2348/69. The receptor-binding domain of intimin polypeptides is located within the c arboxy-terminal 280 amino acids (Int280). Mucosal and systemic vaccination regimens using enterotoxin-based adjuvants were employed to elicit immune r esponses to recombinant Int280 alpha from EPEC strain E2348/69. Mice vaccin ated subcutaneously with Int280 alpha, in the absence of adjuvant, were sig nificantly more resistant to oral challenge with DBS255(pCVD438) but not wi th wild-type C. rodentium. This type-specific immunity could not be overcom e by employing an exposed, highly conserved domain of intimin (Int(388-667) ) as a vaccine. These results show that anti-intimin immune responses can m odulate the outcome (of a C rodentium infection and support the use of inti min as a component of a type-specific EPEC or EHEC vaccine.