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Infection and Immunity, February 2004, p. 996-1003, Vol. 72, No. 2
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.2.996-1003.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Salmonella enterica Serovar Typhimurium RamA, Intracellular Oxidative Stress Response, and Bacterial Virulence

Tahar van der Straaten,1 Laurence Zulianello,1 Angela van Diepen,1 Donald L. Granger,2 Riny Janssen,1 and Jaap T. van Dissel1*

Department of Infectious Diseases, Leiden University Medical Center, 2300 RC Leiden, The Netherlands,1 Division of Infectious Diseases, University of Utah School of Medicine, Salt Lake City, Utah 841322

Received 29 May 2003/ Returned for modification 4 August 2003/ Accepted 28 October 2003

Escherichia coli and Salmonella enterica serovar Typhimurium have evolved genetic systems, such as the soxR/S and marA regulons, to detoxify reactive oxygen species, like superoxide, which are formed as by-products of metabolism. Superoxide also serves as a microbicidal effector mechanism of the host's phagocytes. Here, we investigate whether regulatory genes other than soxR/S and marA are active in response to oxidative stress in Salmonella and may function as virulence determinants. We identified a bacterial gene, which was designated ramA (342 bp) and mapped at 13.1 min on the Salmonella chromosome, that, when overexpressed on a plasmid in E. coli or Salmonella, confers a pleiotropic phenotype characterized by increased resistance to the redox-cycling agent menadione and to multiple unrelated antibiotics. The ramA gene is present in Salmonella serovars but is absent in E. coli. The gene product displays 37 to 52% homology to the transcriptional activators soxR/S and marA and 80 to 100% identity to a multidrug resistance gene in Klebsiella pneumoniae and Salmonella enterica serovar Paratyphi A. Although a ramA soxR/S double null mutant is highly susceptible to intracellular superoxide generated by menadione and displays decreased Mn-superoxide dismutase activity, intracellular survival of this mutant within macrophage-like RAW 264.7 cells and in vivo replication in the spleens in Ityr mice are not affected. We concluded that despite its role in the protective response of the bacteria to oxidative stress in vitro, the newly identified ramA gene, together with soxR/S, does not play a role in initial replication of Salmonella in the organs of mice.

* Corresponding author. Mailing address: Department of Infectious Diseases, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Phone: 31-71-5262613. Fax: 31-71-5266758. E-mail: j.t.van_dissel{at}lumc.nl.

Editor: A. D. O'Brien

Infection and Immunity, February 2004, p. 996-1003, Vol. 72, No. 2
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.2.996-1003.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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