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Infection and Immunity, December 1998, p. 5854-5861, Vol. 66, No. 12
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Modulation of Expression of the ToxR Regulon in Vibrio cholerae by a Member of the Two-Component Family of Response Regulators

Sandy M. Wong,1,2,dagger Patricia A. Carroll,2 Laurence G. Rahme,1,3 Frederick M. Ausubel,4,5 and Stephen B. Calderwood2,6,*

Department of Molecular Biology,1 Infectious Disease Division,2 Shriner's Burns Institute,4 and Department of Surgery,3 Massachusetts General Hospital, Boston, Massachusetts 02114, and Department of Genetics5 and Department of Microbiology and Molecular Genetics,6 Harvard Medical School, Boston, Massachusetts 02115

Received 15 June 1998/Returned for modification 4 August 1998/Accepted 28 September 1998

The ToxRS system in Vibrio cholerae plays a central role in the modulation of virulence gene expression in response to environmental stimuli. An integration of multiple signalling inputs mediated by ToxR, -S, and -T controls virulence gene expression leading to cholera toxin (CT) production. Recently, we identified a new virulence locus, varA (virulence associated regulator), in classical V. cholerae O1 that positively controls transcription of tcpA, the major subunit of the toxin-coregulated pilus (TCP) and the production of CT, two key factors in cholera pathogenesis. The varA locus is a homolog of gacA (originally described for the soil organism Pseudomonas fluorescens), which encodes a conserved global regulator belonging to the family of two-component signal transducing molecules. GacA homologs in a number of diverse gram-negative pathogenic bacterial species have been implicated in controlling the production of diverse virulence factors. varA mutants showed reduced levels of tcpA message and TcpA protein, lacked visible signs of autoagglutination (a phenotype associated with functional TCP), produced decreased levels of CT, and were attenuated in colonizing infant mice. Transcription of varA appears to be independent of ToxR, and overexpression of the regulators tcpPH and toxT from plasmids in the varA mutant restored wild-type levels of CT production and the ability to autoagglutinate. varA represents an additional modulating factor in the coordinate expression of virulence factors in V. cholerae.

* Corresponding author. Mailing address: Infectious Disease Division, Massachusetts General Hospital, Boston, MA 02114. Phone: (617) 726-3811. Fax: (617) 726-7416. E-mail: scalderwood{at}partners.org.

dagger Present address: Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115.

Infection and Immunity, December 1998, p. 5854-5861, Vol. 66, No. 12
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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