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Infection and Immunity, October 2004, p. 5733-5740, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5733-5740.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Escherichia coli Cytotoxic Necrotizing Factor 1 Inhibits Intestinal Epithelial Wound Healing In Vitro after Mechanical Injury

Patrick Brest,1 Laurent Turchi,2 Gaëlle Le'Negrate,1 Frédérick Berto,1 Chimène Moreilhon,3 Bernard Mari,4 Gilles Ponzio,2 and Paul Hofman1,5*

Equipe INSERM 0215,1 Unité INSERM 385,2 Unité INSERM 526,4 Laboratoire de Pathologie Clinique et Experimentale, Facultéde Médecine, Nice,5 Institut de Pharmacologie Moléculaire et Cellulaire, CNRS 6097, Valbonne, France3

Received 14 January 2004/ Returned for modification 26 March 2004/ Accepted 30 June 2004

Cytotoxic necrotizing factor type 1 (CNF1) from Escherichia coli activates the small GTP-binding proteins of the Rho family (Rho, Rac, and Cdc42) by catalyzing their deamidation at a specific glutamine residue. Since RhoA, Rac, and Cdc42 play a pivotal role in cell migration during the early phase of wound repair, we investigated whether CNF1 was able to interfere with wound healing in intestinal epithelial monolayers (T84 cells). After mechanical injury, we found that CNF1 blocks epithelial wound repair within 48 h. This effect was characterized by cell elongation and filopodium formation on the leading edge, in association with permanent phosphorylation of the focal adhesion kinase (FAK) via Rho activation. Moreover, inhibition of Rho kinase with Y-27632 decreased CNF1-mediated permanent FAK phosphorylation, leading to complete restitution of wound repair within 24 h. In addition, we found that CNF1 induced upregulation of mitogen-activated protein kinases (MAPK) activation. Moreover, activation of Rac and MAPK by CNF1 increased matrix metalloproteinase 9 expression in wounded T84 monolayers. Taken together, these results provide evidence that CNF1 strongly impairs intestinal epithelial wound healing.

* Corresponding author. Mailing address: Equipe INSERM 0215, Faculté de Médecine, Avenue de Valombrose, 06107 Nice, Cedex 02, France. Phone: 33 4 93 37 77 59. Fax: 33 4 93 37 77 52. E-mail: hofman{at}unice.fr.

Editor: V. J. DiRita

Infection and Immunity, October 2004, p. 5733-5740, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5733-5740.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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