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Infection and Immunity, November 2008, p. 4804-4813, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00742-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Role of NleH, a Type III Secreted Effector from Attaching and Effacing Pathogens, in Colonization of the Bovine, Ovine, and Murine Gut{triangledown}

Cordula Hemrajani,1 Olivier Marches,1 Siouxsie Wiles,1 Francis Girard,1 Alison Dennis,2 Francis Dziva,3 Angus Best,4 Alan D. Phillips,5 Cedric N. Berger,1 Aurelie Mousnier,1 Valerie F. Crepin,1 Laurens Kruidenier,6 Martin J. Woodward,4 Mark P. Stevens,3 Roberto M. La Ragione,4 Thomas T. MacDonald,2 and Gad Frankel1*

Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ, United Kingdom,1 Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London E1 2AT, United Kingdom,2 Division of Microbiology, Institute for Animal Health, Compton, Newbury, Berkshire RG20 7NN, United Kingdom,3 Department of Food & Environmental Safety, Veterinary Laboratories Agency (Weybridge), Surrey KT15 3NB, United Kingdom,4 Centre for Paediatric Gastroenterology, Royal Free Hospital, London, United Kingdom,5 Immuno-Inflammation CEDD, GlaxoSmithKline Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, United Kingdom6

Received 12 June 2008/ Returned for modification 22 July 2008/ Accepted 16 August 2008

The human pathogen enterohemorrhagic Escherichia coli (EHEC) O157:H7 colonizes human and animal gut via formation of attaching and effacing lesions. EHEC strains use a type III secretion system to translocate a battery of effector proteins into the mammalian host cell, which subvert diverse signal transduction pathways implicated in actin dynamics, phagocytosis, and innate immunity. The genomes of sequenced EHEC O157:H7 strains contain two copies of the effector protein gene nleH, which share 49% sequence similarity with the gene for the Shigella effector OspG, recently implicated in inhibition of migration of the transcriptional regulator NF-{kappa}B to the nucleus. In this study we investigated the role of NleH during EHEC O157:H7 infection of calves and lambs. We found that while EHEC {Delta}nleH colonized the bovine gut more efficiently than the wild-type strain, in lambs the wild-type strain exhibited a competitive advantage over the mutant during mixed infection. Using the mouse pathogen Citrobacter rodentium, which shares many virulence factors with EHEC O157:H7, including NleH, we observed that the wild-type strain exhibited a competitive advantage over the mutant during mixed infection. We found no measurable differences in T-cell infiltration or hyperplasia in colons of mice inoculated with the wild-type or the nleH mutant strain. Using NF-{kappa}B reporter mice carrying a transgene containing a luciferase reporter driven by three NF-{kappa}B response elements, we found that NleH causes an increase in NF-{kappa}B activity in the colonic mucosa. Consistent with this, we found that the nleH mutant triggered a significantly lower tumor necrosis factor alpha response than the wild-type strain.

* Corresponding author. Mailing address: Flowers Building, Imperial College, London SW7 2AZ, United Kingdom. Phone: 44 20 7594 5253. Fax: 44 20 7594 3069. E-mail: g.frankel{at}imperial.ac.uk

{triangledown} Published ahead of print on 25 August 2008.

Editor: A. J. Bäumler

Infection and Immunity, November 2008, p. 4804-4813, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00742-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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