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Infection and Immunity, September 2004, p. 4973-4984, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.4973-4984.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Response Regulator PhoP of Yersinia pseudotuberculosis Is Important for Replication in Macrophages and for Virulence

Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, SUNY at Stony Brook, Stony Brook, New York,¹ E0364 Inserm-Université Lille II (Faculté de Médecine Henri Warembourg), Lille, France²

Received 26 March 2004/ Returned for modification 29 April 2004/ Accepted 3 June 2004

Yersinia pestis and Yersinia pseudotuberculosis are closely related facultative intracellular pathogens. The response regulator PhoP was previously shown to be important for Y. pestis survival in macrophages and for virulence in a murine bubonic plague infection assay. Here the importance of PhoP for Y. pseudotuberculosis pathogenesis was investigated. Y. pseudotuberculosis phoP mutants were unable to replicate in low-Mg²⁺ medium or in macrophages. phoP⁺ Y. pseudotuberculosis strains initiated replication in macrophages after a lag period of 5 h, as shown by fluorescence microscopy and viable count assays. Y. pseudotuberculosis phoP mutants died at a low rate in macrophages; there was no decrease in viability over the first 5 h of infection, and there was a 10-fold decrease in viability between 5 and 24 h of infection. Trafficking of phagosomes containing phoP⁺ or phoP mutant Y. pseudotuberculosis was studied by using immunofluorescence microscopy and cathepsin D as a marker for lysosomes. Phagosomes containing phoP mutant Y. pseudotuberculosis acquired cathepsin D at a higher rate than phagosomes containing phoP⁺ bacteria. However, the increased rate of marker acquisition for phagosomes containing mutant bacteria was only evident 5 h after infection, suggesting that phoP mutants are able to retard phagosome maturation during the lag phase of intracellular growth. The results obtained with a Y. pestis phoP mutant were similar to those described above, except that the rates of intracellular killing and trafficking to cathepsin D-positive vacuoles were significantly higher. A Y. pseudotuberculosis phoP mutant was 100-fold less virulent than the wild-type strain in a murine intestinal infection model, suggesting that survival and replication in macrophages are important for Y. pseudotuberculosis pathogenesis.

Editor: D. L. Burns

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