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Infection and Immunity, November 2003, p. 6510-6525, Vol. 71, No. 11
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.11.6510-6525.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Growth Phase-Dependent Response of Helicobacter pylori to Iron Starvation

D. Scott Merrell,1* Lucinda J. Thompson,2,{dagger}* Charles C. Kim,1 Hazel Mitchell,2 Lucy S. Tompkins,1 Adrian Lee,2 and Stanley Falkow1

Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305,1 School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia2

Received 10 February 2003/ Returned for modification 22 April 2003/ Accepted 30 July 2003

Iron is an essential nutrient that is often found in extremely limited available quantities within eukaryotic hosts. Because of this, many pathogenic bacteria have developed regulated networks of genes important for iron uptake and storage. In addition, it has been shown that many bacteria use available iron concentrations as a signal to regulate virulence gene expression. We have utilized DNA microarray technology to identify genes of the human pathogen Helicobacter pylori that are differentially regulated on a growth-inhibiting shift to iron starvation conditions. In addition, the growth phase-dependent expression of these genes was investigated by examining both exponential and stationary growth phase cultures. We identified known iron-regulated genes, as well as a number of genes whose regulation by iron concentration was not previously appreciated. Included in the list of regulated factors were the known virulence genes cagA, vacA, and napA. We examined the effect of iron starvation on the motility of H. pylori and found that exponential- and stationary-phase cultures responded differently to the stress. We further found that while growing cells are rapidly killed by iron starvation, stationary-phase cells show a remarkable ability to survive iron depletion. Finally, bioinformatic analysis of the predicted promoter regions of the differentially regulated genes led to identification of several putative Fur boxes, suggesting a direct role for Fur in iron-dependent regulation of these genes.

* Corresponding author. Mailing address for D. S. Merrell: Department of Microbiology and Immunology, Stanford University School of Medicine, 299 Campus Dr., Fairchild D051 Stanford, CA 94305. Phone: (650) 725-7161. Fax: (650) 723-1837. E-mail: dmerrell{at}stanford.edu. Present address for L. J. Thompson: Department of Microbiology and Immunology, Stanford University School of Medicine, 299 Campus Dr., Fairchild D051 Stanford, CA 94305. Phone: (650) 723-2671. Fax: (650) 723-1837. E-mail: lucindathompson{at}stanford.edu.

Editor: V. J. DiRita

{dagger} Present address: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305.

Infection and Immunity, November 2003, p. 6510-6525, Vol. 71, No. 11
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.11.6510-6525.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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