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Infection and Immunity, December 2007, p. 5974-5984, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.00750-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Effect of Zinc in Enteropathogenic Escherichia coli Infection{triangledown} ,{dagger}

John K. Crane,1* Tonniele M. Naeher,1 Irina Shulgina,1 Chengru Zhu,2 and Edgar C. Boedeker2

Department of Medicine, Division of Infectious Diseases, University at Buffalo, Buffalo, New York,1 Division of Gastroenterology, University of New Mexico, Albuquerque, New Mexico2

Received 2 June 2007/ Returned for modification 11 July 2007/ Accepted 4 September 2007

Enteropathogenic Escherichia coli (EPEC) infection triggers the release of ATP from host intestinal cells, and the ATP is broken down to ADP, AMP, and adenosine in the lumen of the intestine. Ecto-5'-nucleotidase (CD73) is the main enzyme responsible for the conversion of 5'-AMP to adenosine, which triggers fluid secretion from host intestinal cells and also has growth-promoting effects on EPEC bacteria. In a recent study, we examined the role of the host enzyme CD73 in EPEC infection by testing the effect of ecto-5'-nucleotidase inhibitors. Zinc was a less potent inhibitor of ecto-5'-nucleotidase in vitro than the nucleotide analog {alpha},ß-methylene-ADP, but in vivo, zinc was much more efficacious in preventing EPEC-induced fluid secretion in rabbit ileal loops than {alpha},ß-methylene-ADP. This discrepancy between the in vitro and in vivo potencies of the two inhibitors prompted us to search for potential targets of zinc other than ecto-5'-nucleotidase. Zinc, at concentrations that produced little or no inhibition of EPEC growth, caused a decrease in the expression of EPEC protein virulence factors, such as bundle-forming pilus (BFP), EPEC secreted protein A, and other EPEC secreted proteins, and reduced EPEC adherence to cells in tissue culture. The effects of zinc were not mimicked by other transition metals, such as manganese, iron, copper, or nickel, and the effects were not reversed by an excess of iron. Quantitative real-time PCR showed that zinc reduced the abundance of the RNAs encoded by the bfp gene, by the plasmid-encoded regulator (per) gene, by the locus for the enterocyte effacement (LEE)-encoded regulator (ler) gene, and by several of the esp genes. In vivo, zinc reduced EPEC-induced fluid secretion into ligated rabbit ileal loops, decreased the adherence of EPEC to rabbit ileum, and reduced histopathological damage such as villus blunting. Some of the beneficial effects of zinc on EPEC infection appear to be due to the action of the metal on EPEC bacteria as well as on the host.

* Corresponding author. Mailing address: Division of Infectious Diseases, Room 317, Biomedical Research Bldg., 3435 Main St., Buffalo, NY 14214. Phone: (716) 829-2676. Fax: (716) 829-3889. E-mail: jcrane{at}acsu.buffalo.edu

{triangledown} Published ahead of print on 17 September 2007.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: F. C. Fang

Infection and Immunity, December 2007, p. 5974-5984, Vol. 75, No. 12
0019-9567/07/$08.00+0     doi:10.1128/IAI.00750-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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