The Journal of Experimental Medicine
Janeway's Immunobiology 7th Edition
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Published online April 21, 2008
doi:10.1084/jem.20071698
The Journal of Experimental Medicine, Vol. 205, No. 5, 1121-1132
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Sperandio et al.
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ARTICLE

 Virulent Shigella flexneri subverts the host innate immune response through manipulation of antimicrobial peptide gene expression

Brice Sperandio1,2, Béatrice Regnault3, Jianhua Guo4, Zhi Zhang4, Samuel L. Stanley, Jr.4, Philippe J. Sansonetti1,2, and Thierry Pédron1,2

1 Unité de Pathogénie Microbienne Moléculaire, Département de Biologie Cellulaire et Infection, 2 Unité Institut National de la Santé et de la Recherche Médicale 786, Institut Pasteur, 3 Plateforme Puces à ADN, 75724 Paris Cedex 15, France
4 Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110

CORRESPONDENCE Philippe J. Sansonetti: psanson{at}pasteur.fr

Antimicrobial factors are efficient defense components of the innate immunity, playing a crucial role in the intestinal homeostasis and protection against pathogens. In this study, we report that upon infection of polarized human intestinal cells in vitro, virulent Shigella flexneri suppress transcription of several genes encoding antimicrobial cationic peptides, particularly the human β-defensin hBD-3, which we show to be especially active against S. flexneri. This is an example of targeted survival strategy. We also identify the MxiE bacterial regulator, which controls a regulon encompassing a set of virulence plasmid-encoded effectors injected into host cells and regulating innate signaling, as being responsible for this dedicated regulatory process. In vivo, in a model of human intestinal xenotransplant, we confirm at the transcriptional and translational level, the presence of a dedicated MxiE-dependent system allowing S. flexneri to suppress expression of antimicrobial cationic peptides and promoting its deeper progression toward intestinal crypts. We demonstrate that this system is also able to down-regulate additional innate immunity genes, such as the chemokine CCL20 gene, leading to compromised recruitment of dendritic cells to the lamina propria of infected tissues. Thus, S. flexneri has developed a dedicated strategy to weaken the innate immunity to manage its survival and colonization ability in the intestine.

Abbreviations used: AP-1, activating protein 1; MAPK, mitogen-activated protein kinase; TLR, Toll-like receptor; TTSS, type III secretion system.

Dr. Guo died on 18 January 2008.


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