Two msbB genes encoding maximal acylation of lipid A are required for invasive Shigella flexneri to mediate inflammatory rupture and destruction of the intestinal epithelium

被引:112
作者
d'Hauteville, H
Khan, S
Maskell, DJ
Kussak, A
Weintraub, A
Mathison, J
Ulevitch, RJ
Wuscher, N
Parsot, C
Sansonetti, PJ
机构
[1] Inst Pasteur, Unite Pathogenie Microbienne Mol, F-75724 Paris 15, France
[2] Inst Pasteur, INSERM, U389, F-75724 Paris 15, France
[3] Inst Pasteur, Unite Rech & Expertise Histotechnol & Pathol, F-75724 Paris 15, France
[4] Univ Cambridge, Dept Clin Vet Med, Ctr Vet Sci, Cambridge CB3 0ES, England
[5] Huddinge Univ Hosp, Karolinska Inst, Clin Res Ctr, Stockholm, Sweden
[6] Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
关键词
D O I
10.4049/jimmunol.168.10.5240
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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-alpha 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-alpha 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-a is a major effector of epithelial destruction by Shigella.
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页码:5240 / 5251
页数:12
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