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Infection and Immunity, March 2005, p. 1441-1451, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1441-1451.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Citrobacter rodentium lifA/efa1 Is Essential for Colonic Colonization and Crypt Cell Hyperplasia In Vivo

Jan-Michael A. Klapproth,1* Maiko Sasaki,1 Melanie Sherman,2 Brian Babbin,2 Michael S. Donnenberg,3 Paula J. Fernandes,3 Isabel C. A. Scaletsky,4 Daniel Kalman,2 Asma Nusrat,2 and Ifor R. Williams2

Division of Digestive Diseases,1 Department of Pathology, Emory University, Atlanta, Georgia,2 Division of Infectious Diseases, University of Maryland, Baltimore, Maryland,3 Departamento de Microbiologia, Imunologia, e Parasitologia, Universidade Federal de São Paulo, São Paulo, Brazil4

Received 19 August 2004/ Returned for modification 24 September 2004/ Accepted 4 November 2004

Previously, we have identified a large gene (lifA, for lymphocyte inhibitory factor A) in enteropathogenic Escherichia coli (EPEC) encoding a protein termed lymphostatin that suppresses cytokine expression in vitro. This protein also functions as an adhesion factor for enterohemorrhagic E. coli (EHEC) and Shiga toxin-producing E. coli and is alternatively known as efa1 (EHEC factor for adherence 1). The lifA/efa1 gene is also present in Citrobacter rodentium, an enteric pathogen that causes a disease termed transmissible murine colonic hyperplasia (TMCH), which induces colitis and massive crypt cell proliferation, in mice. To determine if lifA/efa1 is required for C. rodentium-induced colonic pathology in vivo, three in-frame mutations were generated, disrupting the glycosyltransferase (GlM12) and protease (PrMC31) motifs and a domain in between that does not encode any known activity (EID3). In contrast to infection with wild-type C. rodentium, that with any of the lifA/efa1 mutant strains did not induce weight loss or TMCH. Enteric infection with motif mutants GlM12 and PrM31 resulted in significantly reduced colonization counts during the entire 20-day course of infection. In contrast, EID3 was indistinguishable from the wild type during the initial colonic colonization, but cleared rapidly after day 8 of the infection. The colonic epithelium of all infected mice displayed increased epithelial regeneration. However, significantly increased regeneration was observed by day 20 only in mice infected with the wild-type in comparison to those infected with lifA/efa1 mutant EID3. In summary, lifA/efa1 is a critical gene outside the locus for enterocyte effacement that regulates bacterial colonization, crypt cell proliferation, and epithelial cell regeneration.

* Corresponding author. Mailing address: Division of Digestive Diseases, Suite 201, Whitehead Biomedical Research Building, Emory University, 615 Michael St., Atlanta, GA 30345-2173. Phone: (404) 727-5638. Fax: (404) 727-5767. E-mail: jklappr{at}emory.edu.

Editor: J. B. Bliska

Infection and Immunity, March 2005, p. 1441-1451, Vol. 73, No. 3
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.3.1441-1451.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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