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J. Biol. Chem., Vol. 282, Issue 29, 21259-21267, July 20, 2007

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Functional Genomic Studies of Uropathogenic Escherichia coli and Host Urothelial Cells when Intracellular Bacterial Communities Are Assembled^*

Christopher S. Reigstad¹, Scott J. Hultgren, and Jeffrey I. Gordon²

From the Center for Genome Sciences and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 63108

Uropathogenic Escherichia coli (UPEC), the principal cause of urinary tract infection in women, colonizes the gut as well as the genitourinary tract. Studies of mice inoculated with UTI89, a sequenced isolate, have revealed a complex life cycle that includes formation of intracellular bacterial communities (IBCs) in bladder urothelial cells. To understand how UPEC adapts to life in IBCs, we have used GeneChips and/or quantitative reverse transcriptase PCR to study UTI89 recovered from the distal gut of gnotobiotic mice and from IBCs harvested by laser capture microdissection from the bladder urothelium of infected C3H/HeJ female mice. Host responses were characterized in laser capture microdissected urothelial cells that do or do not contain IBCs. The results reveal components of ferric iron acquisition systems in UTI89 that are expressed at significantly higher levels in IBCs compared with the intestine, including the hemin receptor chuA (1,390 ± 188-fold). Localized urothelial responses to IBCs help oppose bacterial salvage of host cell iron (e.g. up-regulation of Tfrc (transferrin receptor) and Lcn2 (lipocalin 2)), facilitate glucose import (e.g. Hk2 (hexokinase 2)), and maintain epithelial structural integrity (e.g. Ivl (involucrin) and Sbsn (suprabasin)). chuA mutants produce significantly smaller IBCs compared with wild type UTI89. This difference was not observed in strains lacking sitA (ABC-type iron/manganese transporter subunit), iroN (salmochelin receptor), hlyA (-hemolysin), or entF (enterobactin synthetase subunit). Together, these studies indicate that heme- and siderophore-associated iron play key roles in IBC development and provide a series of microbial and host biomarkers for comparing UPEC strains isolated from humans.

Received for publication, December 15, 2006 , and in revised form, May 10, 2007.

GeneChip data used in this study are available in the Gene Expression Omnibus (GEO) database (www.ncbi.nlm.nih.gov/projects/geo/). Unmasked raw GeneChip data from E. coli MG1655 and UTI89 harvested from the ceca of gnotobiotic mice are deposited under accession number GSE6426 [NCBI GEO] , in vitro data can be found under accession number GSE6425 [NCBI GEO] , and data from laser-captured mouse urothelium under accession number GSE6419 [NCBI GEO] .

^* This work was supported by National Institutes of Health Grant AR049475. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S7, supplemental Tables S1-S3, and supplemental references.

¹ Recipient of a National Institutes of Health predoctoral fellowship in genomic science (T32HG000045).

² To whom correspondence should be addressed: Center for Genome Sciences, Washington University School of Medicine, Campus Box 8510, 4444 Forest Park Blvd., St. Louis, MO 63108. Tel.: 314-362-7243; Fax: 314-362-362-7047; E-mail: jgordon{at}wustl.edu.

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