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The role of lipopolysaccharide in mucosal protection against shigella flexneri infection


Research objectives and content
Shigella flexneri is the causative agent of endemic bacillary dysentery, a disease primarily afflicting children in developing countries. The pathogenesis of Shigella infection stems from the ability of the organism to invade eukaryotic cells. Once the organism gains entry into the host tissue, intense inflammation and tissue destruction ensue. During natural infection and in experimental models of shigellosis, the immune response against the organism is primarily directed towards epitopes present on Shigella lipopolysaccharide. Additionally, a monoclonal immunoglobulin A (IgA) antibody against a serotype-specific epitope of Shigella LPS is sufficient to protect animals during experimental infection. The objective of this proposal is to understand the mechanisms underlying LPS-specific mucosal immunity against Shigella infection. Two specific objectives form the basis of these studies. The first objective is to examine the ability of anti-LPS IgA to prevent bacterial invasion of eukaryotic cells by blocking bacterial-host cell interactions. Second, the possibility that free LPS taken up by epithelial cells can be blocked by LPS-specific IgA will be examined. Inhibiting either bacterial uptake or the transcytosis of soluble inflammatory mediators such as LPS may prevent the intense inflammatory response and tissue destruction characteristic of Shigella infection. These studies into anti-Shigella mucosal immunity will influence the development and design of vaccines against S. flexneri infection.
Training content (objective, benefit and expected impact)
Diarrheal diseases cause considerable morbidity and mortality throughout the world. The impact of diarrheal disease is greatest in children, particularly in developing countries. It is estimated that five million children die yearly in developing countries as a result of dehydration caused by diarrhea. Shigellae are one of the most important etiologic agents causing endemic diarrheal disease. S. flexneri, which is the most prevalent of the genus, causes dysentery characterized by severe diarrhea with the presence of blood and mucus in the stools. At present, an ideal vaccine against S. flexneri infection has not been produced. The design and development of improved vaccines against Shigella will based on an increased understanding of host-microbe interactions during Shigella infection. The studies outlined in this proposal will contribute to our general understanding of the mucosal immune response to S. flexneri infection. Additionally, these studies will likely impact on the current design of vaccines against this enteric pathogen.
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Institut Pasteur
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28 rue du Docteur Roux
75724 Paris

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