title: Intimin-specific immune responses prevent bacterial colonization by the attaching-effacing pathogen Citrobacter rodentium.
abstract: 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 rodentium. 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 long-lived humoral immune responses in C. rodentium-infected mice. Mice infected with C. rodentium developed robust acquired immunity and were resistant to reinfection with wild-type C. rodentium or a C. rodentium derivative, DBS255(pCVD438), which expressed intimin derived from EPEC strain E2348/69. The receptor-binding domain of intimin polypeptides is located within the carboxy-terminal 280 amino acids (Int280). Mucosal and systemic vaccination regimens using enterotoxin-based adjuvants were employed to elicit immune responses to recombinant Int280alpha from EPEC strain E2348/69. Mice vaccinated subcutaneously with Int280alpha, in the absence of adjuvant, were significantly more resistant to oral challenge with DBS255(pCVD438) but not with wild-type C. rodentium. This type-specific immunity could not be overcome by employing an exposed, highly conserved domain of intimin (Int388-667) as a vaccine. These results show that anti-intimin immune responses can modulate the outcome of a C. rodentium infection and support the use of intimin as a component of a type-specific EPEC or EHEC vaccine.
authors.affiliation: Centre for Molecular Microbiology and Infection, Department of Biochemistry, Imperial College of Science, Technology and Medicine, South Kensington, London SW7 2AZ, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Ghaem-Maghami
authors.forename: C P
authors.initials: CP
authors.lastname: Simmons
authors.forename: S
authors.initials: S
authors.lastname: Daniell
authors.forename: M
authors.initials: M
authors.lastname: Pizza
authors.forename: D
authors.initials: D
authors.lastname: Lewis
authors.forename: G
authors.initials: G
authors.lastname: Frankel
authors.forename: G
authors.initials: G
authors.lastname: Dougan
mesh_terms: D018829:Adhesins, Bacterial; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001425:Bacterial Outer Membrane Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins; D016971:Citrobacter freundii / Q000254:growth & development / Q000276:immunology*; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000517:prevention & control*; D029968:Escherichia coli Proteins; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D011956:Receptors, Cell Surface / Q000276:immunology; D014611:Vaccination
chemical_list: D018829:Adhesins, Bacterial; D000907:Antibodies, Bacterial; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D002352:Carrier Proteins; C087863:EaeB protein, E coli; D029968:Escherichia coli Proteins; C102051:EspA protein, E coli; D011956:Receptors, Cell Surface; C109287:Tir protein, E coli; C073819:eaeA protein, E coli