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Infection and Immunity, August 2004, p. 4654-4661, Vol. 72, No. 8
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.8.4654-4661.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Role of the Two-Component Regulator CpxAR in the Virulence of Salmonella enterica Serotype Typhimurium

Sue Humphreys,¹ Gary Rowley,¹ Andrew Stevenson,¹ Muna F. Anjum,² Martin J. Woodward,² Stephen Gilbert,^1, Jan Kormanec,³ and Mark Roberts^1*

Molecular Bacteriology Group, Institute of Comparative Medicine, Department of Veterinary Pathology, Glasgow University Veterinary School, Bearsden Road, Glasgow G61 1QH,¹ Department of Food and Environmental Safety, Veterinary Laboratories Agency (Weybridge), Addlestone, Surrey KT15 3NB, United Kingdom,² Institute of Molecular Biology, Centre of Excellence for Molecular Medicine, Slovak Academy of Science, 845 51 Bratislava, Slovak Republic³

Received 17 February 2004/ Returned for modification 30 March 2004/ Accepted 12 May 2004

The CpxAR (Cpx) two-component regulator controls the expression of genes in response to a variety of environmental cues. The Cpx regulator has been implicated in the virulence of several gram-negative pathogens, although a role for Cpx in vivo has not been demonstrated directly. Here we investigate whether positive or negative control of gene expression by Cpx is important for the pathogenesis of Salmonella enterica serotype Typhimurium. The Cpx signal pathway in serotype Typhimurium was disrupted by insertional inactivation of the cpxA and cpxR genes. We also constitutively activated the Cpx pathway by making an internal in-frame deletion in cpxA (a cpxA* mutation). Activation of the Cpx pathway inhibited induction of the envelope stress response pathway controlled by the alternative sigma factor ^E (encoded by rpoE). Conversely, the Cpx pathway was highly up-regulated (>40-fold) in a serotype Typhimurium rpoE mutant. The cpxA* mutation, but not the cpxA or the cpxR mutation, significantly reduced the capacity of serotype Typhimurium to adhere to and invade eucaryotic cells, although intracellular replication was not affected. The cpxA and cpxA* mutations significantly impaired the ability of serotype Typhimurium to grow in vivo in mice. To our knowledge, this is the first demonstration that the Cpx system is important for a bacterial pathogen in vivo.

Editor: J. T. Barbieri

Present address. 23 Savage Rd., Bridlington YO15 3HW, United Kingdom.

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