This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stähler, F. N. Articles by Bereswill, S. Search for Related Content PubMed PubMed Citation Articles by Stähler, F. N. Articles by Bereswill, S.

 Previous Article  |  Next Article 

Infection and Immunity, July 2006, p. 3845-3852, Vol. 74, No. 7
0019-9567/06/$08.00+0     doi:10.1128/IAI.02025-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Novel Helicobacter pylori CznABC Metal Efflux Pump Is Required for Cadmium, Zinc, and Nickel Resistance, Urease Modulation, and Gastric Colonization

Department of Microbiology and Hygiene, Institute of Medical Microbiology and Hygiene, University Hospital Freiburg, Hermann-Herder-Str. 11, D-79104 Freiburg, Germany,¹ Ludwig-Maximilians University Munich, Max von Pettenkofer Institute for Hygiene and Medical Microbiology, Munich, Germany,² Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands³

Received 16 December 2005/ Returned for modification 7 February 2006/ Accepted 5 April 2006

Maintaining metal homeostasis is crucial for the adaptation of Helicobacter pylori to the gastric environment. Iron, copper, and nickel homeostasis has recently been demonstrated to be required for the establishment of H. pylori infection in animal models. Here we demonstrate that the HP0969-0971 gene cluster encoding the Czc-type metal export pump homologs HP0969, HP0970, and the H. pylori-specific protein HP0971 forms part of a novel H. pylori metal resistance determinant, which is required for gastric colonization and for the modulation of urease activity. Insertional mutagenesis of the HP0971, HP0970, or HP0969 genes in H. pylori reference strain 26695 resulted in increased sensitivity to cadmium, zinc, and nickel (czn), suggesting that the encoded proteins constitute a metal-specific export pump. Accordingly, the genes were designated cznC (HP0971), cznB (HP0970), and cznA (HP0969). The CznC and CznA proteins play a predominant role in nickel homeostasis, since only the cznC and cznA mutants but not the cznB mutant displayed an 8- to 10-fold increase in urease activity. Nickel-specific affinity chromatography demonstrated that recombinant versions of CznC and CznB can bind to nickel and that the purified CznB protein interacted with cadmium and zinc, since both metals competitively inhibited nickel binding. Finally, single cznA, cznB, and cznC mutants did not colonize the stomach in a Mongolian gerbil-based animal model. This demonstrates that the metal export functions of H. pylori cznABC are essential for gastric colonization and underlines the extraordinary importance of metal ion homeostasis for the survival of H. pylori in the gastric environment.

Editor: J. B. Bliska

Present address for S. Bereswill: Humboldt University, Charité University Medicine Berlin, Charité Campus Mitte, Institute for Microbiology and Hygiene, Dorotheenstrasse 96, D-10117 Berlin, Germany.

This article has been cited by other articles:

• Coudeyras, S., Nakusi, L., Charbonnel, N., Forestier, C. (2008). A Tripartite Efflux Pump Involved in Gastrointestinal Colonization by Klebsiella pneumoniae Confers a Tolerance Response to Inorganic Acid. Infect. Immun. 76: 4633-4641 [Abstract] [Full Text]  
• Mirete, S., de Figueras, C. G., Gonzalez-Pastor, J. E. (2007). Novel Nickel Resistance Genes from the Rhizosphere Metagenome of Plants Adapted to Acid Mine Drainage. Appl. Environ. Microbiol. 73: 6001-6011 [Abstract] [Full Text]  
• Seshadri, S., Benoit, S. L., Maier, R. J. (2007). Roles of His-Rich Hpn and Hpn-Like Proteins in Helicobacter pylori Nickel Physiology. J. Bacteriol. 189: 4120-4126 [Abstract] [Full Text]  
• Megraud, F., Lehours, P. (2007). Helicobacter pylori Detection and Antimicrobial Susceptibility Testing. Clin. Microbiol. Rev. 20: 280-322 [Abstract] [Full Text]