KEEPS WATCH AGAINST MICROBES
A new target for new anti-inflammatory drugs?
Collaboration between a number of teams* at the Institut Pasteur has made it possible to throw light on a mechanism which enables epithelial cells to detect the presence of microbes inside themselves, and to trigger a defensive reaction. This mechanism, published in Science, offers a new route for perfecting drugs for inflammatory diseases of the intestines and the lungs.
Epithelial cells in the mucosae (intestine, lungs, etc.) are our first line of defence against micro-organisms. The researchers at the Pasteur, led by the teams of Dana Philpott* and Philippe Sansonetti*, have thrown new light on a system, at the level of the intestinal barrier, to watch for accidental breaking through this barrier by bacteria. When this system is alerted, the epithelial cells start to produce soluble factors (cytokines, chemokines) in order to destroy the micro-organisms in question. By throwing new light upon the basis of this inflammatory reaction, there is no room for doubt that the researchers have opened up a new pathway for perfecting drugs for inflammatory mechanisms of the intestine (infectious colitis, ulcerative colitis, Crohn's disease), or of the lungs (asthma,cystic fibrosis).
They have shown that Nod1, a molecule present in the interior of the epithelial cells, detects peptidoglycan, a specific component in the cell wall of bacteria, and when it does so, recognition triggers off an inflammatory reaction. Epithelial cells without Nod1 in the presence of the same bacteria do not trigger the inflammatory reaction. Nod1 is therefore crucial in the perception of the invading bacterial agent. This seems to be the only sentinel molecule in the epithelial barrier which enables the intracellular recognition of bacteria and plays a key role in the innate immune defences.
Nod1 and the bacterial peptidoglycan which it recognises could be targets for controlling inflammation at the level of the epithelial cells.
The researchers are continuing to study this mechanism by analysing how Nod1 controls the equilibrium of commensal or pathogenic bacteria on the surface of epithelial cells, and how it sets up the mechanisms which regulate our defences.
* Source : "Nod1 detects a unique muropeptide from Gram-negative bacterial peptidoglycan" : Science, 6 June 2003
Stephen E. Girardin (1), Ivo G. Boneca (2), Leticia A.M. Carneiro (3), Aude Antignac (4), Muguette Jéhanno (3), Jérôme Viala (3), Karsten Tedin (5), Muhamed Kheir Taha (4), Agnès Labigne (2), Ulrich Zähringer (6), Anthony J. Coyle (7), Peter S. DiStefano (7), John Bertin (7), Philippe J. Sansonetti (1) and Dana J. Philpott (3)
1 Molecular Microbial Pathogenesis
Unit, INSERM U 389, Institut Pasteur
2 Pathogenesis of Mucosal Bacteria Unit, Institut Pasteur
3 Innate Immunity and Cell Signalling Group, Institut Pasteur
4 Neisseria Unit, Institut Pasteur
5 Institut für MiKrobiologie und Tierseuchen, Freie Universität Berlin, Allemagne
6 Division of Immunochemistry, Research Center Borstel, Center for Medicine and Biosciences, Borstel, Germany
7 Millenium Pharmaceuticals Inc., Cambridge, USA
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