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J. Biol. Chem., Vol. 282, Issue 20, 15065-15072, May 18, 2007

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Functional Genomic Studies of the Intestinal Response to a Foodborne Enteropathogen in a Humanized Gnotobiotic Mouse Model^*

Marc Lecuit¹², Justin L. Sonnenburg¹, Pascale Cossart³, and Jeffrey I. Gordon, Supported by National Institutes of Health Grant DK30292 and the Ellison Foundation⁴

From the Center for Genome Sciences, Washington University School of Medicine, St. Louis, Missouri 63108 and the Bacteria Cell Interactions Unit, Institut Pasteur, INSERM U604, and INRA, USC2020, Paris F-75015, France

Members of the genus Listeria provide a model for defining host responses to invasive foodborne enteropathogens. Active translocation of Listeria monocytogenes across the gut epithelial barrier is mediated by interaction of bacterial internalin (InlA) and its species-specific host receptor, E-cadherin, whereas translocation across Peyer's patches through M-cells is InlA-independent. To define microbial determinants and molecular correlates of the host response to translocation via these two routes, we colonized germ-free transgenic mice expressing the human enterocyte-associated E-cadherin receptor with wild-type (WT) or mutant L. monocytogenes strains, or its nonpathogenic noninvasive relative Listeria innocua, or with Bacteroides thetaiotaomicron, a prominent gut symbiont. Mouse Gene-Chips, combined with Ingenuity Pathway software, were used to identify canonical signaling pathways that comprise the response to WT L. monocytogenes versus the other species. Gain- and loss-of-function experiments with L. innocua and L. monocytogenes, respectively, demonstrated that the 773-member transcriptional signature of the response to WT L. monocytogenes is largely conserved in the inlA mutant. Internalin-dependent responses include down-regulation of gene networks involved in various aspects of lipid, amino acid, and energy metabolism and up-regulation of immunoinflammatory responses. The host response is markedly attenuated in a listeriolysin-deficient (hly) mutant despite its ability to be translocated to the lamina propria. Together, these studies establish that hly, rather than bacterial invasion of the lamina propria mediated by InlA, is a dominant determinant of the intensity of the host response to L. monocytogenes infection via the oral route.

Received for publication, November 27, 2006 , and in revised form, March 27, 2007.

^* 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-S5 and Tables S1-S8.

¹ These authors contributed equally to this work.

² Supported by a European Molecular Biology Organization fellowship and the Philippe Foundation. Present address: Avenir INSERM U604, Bacteria Cell Interactions Unit, Institut Pasteur, and Dept. of Infectious Diseases and Tropical Medicine, Necker-Enfants Malades Hospital, René Descartes Paris-5 University, Paris 75015, France.

³ A Howard Hughes Medical Institute international research scholar.

⁴ To whom correspondence should be addressed: Center for Genome Sciences, Washington University School of Medicine, 4444 Forest Park Blvd., Campus Box 8510, St. Louis, MO 63108. Tel.: 314-362-7243; Fax: 314-362-7047; E-mail: jgordon{at}wustl.edu.

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