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Infection and Immunity, April 2003, p. 2102-2109, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.2102-2109.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Salmonella Infection Induces a Hypersecretory Phenotype in Human Intestinal Xenografts by Inducing Cyclooxygenase 2

Lone S. Bertelsen, Guenther Paesold, Lars Eckmann, and Kim E. Barrett*

Division of Gastroenterology, Department of Medicine, UCSD School of Medicine, San Diego, California 92103-8414

Received 14 June 2002/ Returned for modification 5 September 2002/ Accepted 16 December 2002

Enteric Salmonella infection is accompanied by inflammation and diarrhea, and yet little is known about its effects on intestinal epithelial physiology. Since species differences limit the utility of animal tissues and cell lines lack relevant cell-cell interactions, we have used a human model of fetal intestine grown as xenografts in SCID mice. We investigated here the effects of Salmonella enterica serovar Typhimurium SL1344 on xenograft ion transport. Harvested xenografts were stripped of seromuscular layers by blunt dissection, infected with Salmonella, and mounted in Ussing chambers. Salmonella infection for 1 h increased baseline ion transport without altering tissue conductance or morphology. The increased transport was blocked by the cyclooxygenase inhibitor, indomethacin, or the specific Cox-2 inhibitor, NS-398. Further, xenografts infected for 2 h showed increased secretory responses to the calcium-dependent agonist, carbachol, and the cyclic AMP-dependent agonists prostaglandin E2 (PGE2) and forskolin, which were blocked by indomethacin. Western blot experiments revealed that infection was accompanied by increased cyclooxygenase 2 (Cox-2) expression, with no change in Cox-1 levels. Immunoassay demonstrated basolateral PGE2 release, which was inhibited by indomethacin. Histological examination of infected xenografts illustrated that upregulated Cox-2 expression was restricted to the epithelium and that little or no invasion of the tissue by Salmonella occurred for up to 2 h. In summary, Salmonella infection rapidly increases Cox-2 expression in human intestinal tissue, accounting for increased epithelial ion transport characteristic of infectious diarrhea.

* Corresponding author. Mailing address: Division of Gastroenterology, UCSD Medical Center, 8414, 200 W. Arbor Dr., San Diego, CA 92103-8414. Phone: (619) 543-3726. Fax: (619) 543-6969. E-mail: kbarrett{at}ucsd.edu.

Editor: B. B. Finlay

Infection and Immunity, April 2003, p. 2102-2109, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.2102-2109.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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