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Infection and Immunity, June 2000, p. 3419-3425, Vol. 68, No. 6
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

The Response Regulator PhoP Is Important for Survival under Conditions of Macrophage-Induced Stress and Virulence in Yersinia pestis

Petra C. F. Oyston,¹ Nick Dorrell,² Kerstin Williams,² Shu-Rui Li,^2, Michael Green,¹ Richard W. Titball,¹ and Brendan W. Wren^2,*

Defence Evaluation and Research Agency, Salisbury, Wiltshire, SP4 0JQ,¹ and Pathogen Molecular Biology and Biochemistry Unit, Department of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, WC1E 7HT,² United Kingdom

Received 8 November 1999/Returned for modification 6 January 2000/Accepted 8 March 2000

The two-component regulatory system PhoPQ has been identified in many bacterial species. However, the role of PhoPQ in regulating virulence gene expression in pathogenic bacteria has been characterized only in Salmonella species. We have identified, cloned, and sequenced PhoP orthologues from Yersinia pestis, Yersinia pseudotuberculosis, and Yersinia enterocolitica. To investigate the role of PhoP in the pathogenicity of Y. pestis, an isogenic phoP mutant was constructed by using a reverse-genetics PCR-based strategy. The protein profiles of the wild-type and phoP mutant strains, grown at either 28 or 37°C, revealed more than 20 differences, indicating that PhoP has pleiotrophic effects on gene expression in Y. pestis. The mutant showed a reduced ability to survive in J774 macrophage cell cultures and under conditions of low pH and oxidative stress in vitro. The mean lethal dose of the phoP mutant in mice was increased 75-fold in comparison with that of the wild-type strain, indicating that the PhoPQ system plays a key role in regulating the virulence of Y. pestis.

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^* Corresponding author. Mailing address: Pathogen Molecular Biology and Biochemistry Unit, Department of Infectious Diseases, London School of Hygiene and Tropical Medicine, Keppel St., London, WC1E 7HT, United Kingdom. Phone: 44 (0)171 927 2288. Fax: 44 (0)171 636 8739. E-mail: brendan.wren{at}lshtm.ac.uk.

Present address: Academic Department of Surgery, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Whitechapel, London, United Kingdom.

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Infection and Immunity, June 2000, p. 3419-3425, Vol. 68, No. 6
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

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