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Infection and Immunity, May 2008, p. 2051-2062, Vol. 76, No. 5
0019-9567/08/$08.00+0     doi:10.1128/IAI.01557-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Role of RppA in the Regulation of Polymyxin B Susceptibility, Swarming, and Virulence Factor Expression in Proteus mirabilis

Won-Bo Wang,² I-Chun Chen,¹ Sin-Sien Jiang,¹ Hui-Ru Chen,¹ Chia-Yu Hsu,¹ Po-Ren Hsueh,³ Wei-Bin Hsu,² and Shwu-Jen Liaw^1,3*

Department and Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology,¹ Graduate Institute of Microbiology, College of Medicine, National Taiwan University,² Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China³

Received 26 November 2007/ Returned for modification 10 January 2008/ Accepted 20 February 2008

Proteus mirabilis, a human pathogen that frequently causes urinary tract infections, is intrinsically highly resistant to cationic antimicrobial peptides, such as polymyxin B (PB). To explore the mechanisms underlying P. mirabilis resistance to PB, a mutant which displayed increased (>160-fold) sensitivity to PB was identified by transposon mutagenesis. This mutant was found to have Tn5 inserted into a novel gene, rppA. Sequence analysis indicated that rppA may encode a response regulator of the two-component system and is located upstream of the rppB gene, which may encode a membrane sensor kinase. An rppA knockout mutant of P. mirabilis had an altered lipopolysaccharide (LPS) profile. The LPS purified from the rppA knockout mutant could bind more PB than the LPS purified from the wild type. These properties of the rppA knockout mutant may contribute to its PB-sensitive phenotype. The rppA knockout mutant exhibited greater swarming motility and cytotoxic activity and expressed higher levels of flagellin and hemolysin than the wild type, suggesting that RppA negatively regulates swarming, hemolysin expression, and cytotoxic activity in P. mirabilis. PB could modulate LPS synthesis and modification, swarming, hemolysin expression, and cytotoxic activity in P. mirabilis through an RppA-dependent pathway, suggesting that PB could serve as a signal to regulate RppA activity. Finally, we demonstrated that the expression of rppA was up-regulated by a low concentration of PB and down-regulated by a high concentration of Mg²⁺. Together, these data highlight the essential role of RppA in regulating PB susceptibility and virulence functions in P. mirabilis.

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* Corresponding author. Mailing address: Department and Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, 10016, No. 1, Chang-Te Street, Taipei, Taiwan, Republic of China. Phone: 886-02-23123456, ext. 6911. Fax: 886-02-23711574. E-mail: sjliaw{at}ntu.edu.tw

Published ahead of print on 3 March 2008.

Editor: J. B. Bliska

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Infection and Immunity, May 2008, p. 2051-2062, Vol. 76, No. 5
0019-9567/08/$08.00+0     doi:10.1128/IAI.01557-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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