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Infection and Immunity, September 2006, p. 5106-5113, Vol. 74, No. 9
0019-9567/06/$08.00+0     doi:10.1128/IAI.00376-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Uropathogenic Escherichia coli Induces Extrinsic and Intrinsic Cascades To Initiate Urothelial Apoptosis

David J. Klumpp,1,2* Matthew T. Rycyk,1,{dagger} Michael C. Chen,1 Praveen Thumbikat,1 Shomit Sengupta,1,{ddagger} and Anthony J. Schaeffer1

Departments of Urology,1 Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 606112

Received 7 March 2006/ Returned for modification 24 April 2006/ Accepted 28 June 2006

A murine model of urinary tract infection identified urothelial apoptosis as a key event in the pathogenesis mediated by uropathogenic Escherichia coli (UPEC), yet the mechanism of this important host response is not well characterized. We employed a culture model of UPEC-urothelium interactions to examine the biochemical events associated with urothelial apoptosis induced by the UPEC strain NU14. NU14 induced DNA cleavage within 5 h that was inhibited by the broad caspase inhibitor ZVAD, and urothelial caspase 3 activity was induced within 3 h of exposure to type 1 piliated NU14 and was dependent upon interactions mediated by the type 1 pilus adhesin FimH. Flow cytometry experiments using chloromethyl-X-rosamine and Indo-1 revealed FimH-dependent mitochondrial membrane depolarization and elevated [Ca2+]in, respectively, indicating activation of the intrinsic apoptotic pathway. Consistent with this possibility, overexpression of BclXL inhibited NU14 activation of caspase 3. Immunoblotting, caspase inhibitors, and caspase activity assays implicated both caspase 2 and caspase 8 in apoptosis, suggesting the involvement of the intrinsic and extrinsic apoptotic cascades. To reconcile the apparent activation of both extrinsic and intrinsic pathways, we examined Bid-green fluorescent protein localization and observed translocation from the cytosol to mitochondria in response to either NU14 or purified FimH. These data suggest that FimH acts as a tethered toxin of UPEC that activates caspase-dependent urothelial apoptosis via direct induction of the extrinsic pathway and that the intrinsic pathway is activated indirectly as a result of coupling by caspase 8-mediated Bid cleavage.

* Corresponding author. Mailing address: Department of Urology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611. Phone: (312) 908-1996. Fax: (312) 908-7278. E-mail: d-klumpp{at}northwestern.edu.

Editor: J. B. Bliska

{dagger} Present address: Reddy US Therapeutics, Norcross, GA 30071.

{ddagger} Present address: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.

Infection and Immunity, September 2006, p. 5106-5113, Vol. 74, No. 9
0019-9567/06/$08.00+0     doi:10.1128/IAI.00376-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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