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Infection and Immunity, December 2007, p. 5867-5876, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.00559-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

High-Affinity Zn2+ Uptake System ZnuABC Is Required for Bacterial Zinc Homeostasis in Intracellular Environments and Contributes to the Virulence of Salmonella enterica{triangledown}

Serena Ammendola,1 Paolo Pasquali,2 Claudia Pistoia,2 Paola Petrucci,2 Patrizia Petrarca,1 Giuseppe Rotilio,1,3 and Andrea Battistoni1*

Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy,1 Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità, 00161 Rome, Italy,2 Research Center, IRCCS San Raffaele "La Pisana," 00163, Rome, Italy3

Received 18 April 2007/ Returned for modification 22 May 2007/ Accepted 11 September 2007

To investigate the relevance of zinc in host-pathogen interactions, we have constructed Salmonella enterica mutant strains in which the znuA gene, which encodes the periplasmic component of the ZnuABC high-affinity Zn2+ transporter, was deleted. This mutation does not alter the ability of Salmonella to grow in rich media but drastically reduces its ability to multiply in media deprived of zinc. In agreement with this phenotype, ZnuA accumulates only in bacteria cultivated in environments poor in zinc. In spite of the nearly millimolar intracellular concentration of zinc, we have found that znuA is highly expressed in intracellular salmonellae recovered either from cultivated cells or from the spleens of infected mice. We have also observed that znuA mutants are impaired in their ability to grow in Caco-2 epithelial cells and that bacteria starved for zinc display decreased ability to multiply in phagocytes. A dramatic reduction in the pathogenicity of the znuA mutants was observed in Salmonella-susceptible (BALB/c) or Salmonella-resistant (DBA-2) mice infected intraperitoneally or orally. This study shows that the amount of free metals available for bacterial growth within the infected animal is limited, despite the apparent elevated concentration of free metals within cells and in plasma and suggests that Salmonella exploits the ZnuABC zinc transporter to maximize zinc availability in such conditions. These results shed new light on the complex functions of zinc in vertebrate and bacterial physiology and pave the way for a better comprehension of pathogenic mechanisms in Salmonella infections.

* Corresponding author. Mailing address: Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Roma, Italy. Phone: 39-0672594372. Fax: 39-0672594311. E-mail: andrea.battistoni{at}uniroma2.it

{triangledown} Published ahead of print on 8 October 2007.

Editor: J. B. Bliska

Infection and Immunity, December 2007, p. 5867-5876, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.00559-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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