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Infection and Immunity, November 2008, p. 5247-5256, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00770-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

RegA, an AraC-Like Protein, Is a Global Transcriptional Regulator That Controls Virulence Gene Expression in Citrobacter rodentium{triangledown}

Emily Hart,1,2,{dagger} Ji Yang,1,2,{dagger} Marija Tauschek,1,2 Michelle Kelly,1 Matthew J. Wakefield,3 Gad Frankel,4 Elizabeth L. Hartland,1,2 and Roy M. Robins-Browne1,2*

Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia,1 Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia,2 Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia,3 Division of Cell and Molecular Biology, Imperial College London, London SW7 2AZ, United Kingdom4

Received 19 June 2008/ Accepted 24 August 2008

Citrobacter rodentium is an attaching and effacing pathogen which causes transmissible colonic hyperplasia in mice. Infection with C. rodentium serves as a model for infection of humans with enteropathogenic and enterohemorrhagic Escherichia coli. To identify novel colonization factors of C. rodentium, we screened a signature-tagged mutant library of C. rodentium in mice. One noncolonizing mutant had a single transposon insertion in an open reading frame (ORF) which we designated regA because of its homology to genes encoding members of the AraC family of transcriptional regulators. Deletion of regA in C. rodentium resulted in markedly reduced colonization of the mouse intestine. Examination of lacZ transcriptional fusions using promoter regions of known and putative virulence-associated genes of C. rodentium revealed that RegA strongly stimulated transcription of two newly identified genes located close to regA, which we designated adcA and kfcC. The cloned adcA gene conferred autoaggregation and adherence to mammalian cells to E. coli strain DH5{alpha}, and a kfc mutation led to a reduction in the duration of intestinal colonization, but the kfc mutant was far less attenuated than the regA mutant. These results indicated that other genes of C. rodentium whose expression required activation by RegA were required for colonization. Microarray analysis revealed a number of RegA-regulated ORFs encoding proteins homologous to known colonization factors. Transcription of these putative virulence determinants was activated by RegA only in the presence of sodium bicarbonate. Taken together, these results show that RegA is a global regulator of virulence in C. rodentium which activates factors that are required for intestinal colonization.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, The University of Melbourne, Victoria 3010, Australia. Phone: 61 3 8344 8275. Fax: 61 3 8344 8276. E-mail: r.browne{at}unimelb.edu.au

{triangledown} Published ahead of print on 2 September 2008.

Editor: S. R. Blanke

{dagger} E.H. and J.Y. contributed equally to this work.

Infection and Immunity, November 2008, p. 5247-5256, Vol. 76, No. 11
0019-9567/08/$08.00+0     doi:10.1128/IAI.00770-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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