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Infection and Immunity, September 2001, p. 5597-5605, Vol. 69, No. 9
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.9.5597-5605.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Intimin-Specific Immune Responses Prevent Bacterial Colonization by the Attaching-Effacing Pathogen Citrobacter rodentium

Marjan Ghaem-Maghami,1 Cameron P. Simmons,1,* Sarah Daniell,1 Mariagrazia Pizza,2 David Lewis,3 Gad Frankel,1 and Gordon Dougan1

Centre for Molecular Microbiology and Infection, Department of Biochemistry, Imperial College of Science, Technology and Medicine, South Kensington, London SW7 2AZ,1 and Department of Infectious Diseases, St. Georges Hospital Medical School, Tooting, London SW17 ORE,3 United Kingdom, and The Chiron Vaccines Immunological Research Institute, Siena, 53100, Italy2

Received 29 January 2001/Returned for modification 21 March 2001/Accepted 4 June 2001

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.

* Corresponding author. Mailing address: Department of Biochemistry, Imperial College of Science, Technology, and Medicine, South Kensington, London SW7 2AZ, United Kingdom. Phone: 0044-20-75945254. Fax: 0044-20-75945255. E-mail: c.simmons{at}ic.ac.uk.

Infection and Immunity, September 2001, p. 5597-5605, Vol. 69, No. 9
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.9.5597-5605.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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