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* Unité de Pathogénie Microbienne Moléculaire and Institut National de la Santé et de la Recherche Médicale, Unité 389, and
Unité de Recherche et d’Expertise Histotechnologie et Pathologie, Institut Pasteur, Paris, France; and
Department of Clinical Veterinary Medicine, Center for Veterinary Science, University of Cambridge, Cambridge, United Kingdom;
Karolinska Institute, Clinical Research Center, Huddinge University Hospital, Stockholm, Sweden; and
¶ Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037
Shigella flexneri is a Gram-negative pathogen that
invades and causes inflammatory destruction of the human colonic
epithelium, thus leading to bloody diarrhea and dysentery. A type III
secretion system that delivers effector proteins into target eukaryotic
cells is largely responsible for cell and tissue invasion. However, the
respective role of this invasive phenotype and of lipid A, the
endotoxin of the Shigella LPS, in eliciting the
inflammatory cascade that leads to rupture and destruction of the
epithelial barrier, was unknown. We investigated whether genetic
detoxification of lipid A would cause significant alteration in
pathogenicity. We showed that S. flexneri has two
functional msbB genes, one carried by the
chromosome (msbB1) and the other by the virulence
plasmid (msbB2), the products of which act in complement
to produce full acyl-oxy-acylation of the myristate at the 3' position
of the lipid A glucosamine disaccharide. A mutant in which both the
msbB1 and msbB2 genes have been
inactivated was impaired in its capacity to cause TNF-
production by
human monocytes and to cause rupture and inflammatory destruction of
the epithelial barrier in the rabbit ligated intestinal loop model of
shigellosis, indicating that lipid A plays a significant role in
aggravating inflammation that eventually destroys the intestinal
barrier. In addition, neutralization of TNF- during invasion by the
wild-type strain strongly impaired its ability to cause rupture and
inflammatory destruction of the epithelial lining, thus indicating that
TNF- is a major effector of epithelial destruction by
Shigella.
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