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BREACHING THE INTESTINAL WALL
Pathogen crosses intestinal barrier with help from a surface protein
MAUREEN ROUHI
Infection with listeria monocytogenes from contaminated food causes flulike symptoms. If untreated, these worsen to gastroenteritis, convulsions, even spontaneous abortions. From the mouth, the pathogen travels to the stomach, crosses the intestine, and spreads through the bloodstream. How it breaks through the intestine has been a subject of much research.
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DANGEROUS Listeria monocytogenes |
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PHOTO RESEARCHERS INC. |
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A new study shows that the pathogen breaches the intestinal barrier through a surface protein that binds to a human protein on epithelial cells of the intestine. The work was carried out by Pascale Cossart and coworkers at the Pasteur Institute, in Paris [Science, 292, 1722 (2001)].
Previous in vitro studies had shown that the bacterial protein, called internalin, interacts with a receptor called E-cadherin on intestinal cells. Using animal models of the oral infection, the new study confirms that this protein-protein interaction is key to the pathogen's virulence.
When the two proteins bind, the bacterium is "yanked inside the epithelial cells, which presumably lets the bacterium pass through the intestinal barrier and reach deeper tissue," B. Brett Finlay, a biotechnology professor at the University of British Columbia, tells C&EN.
What's still unknown is how the bacterium finds E-cadherin, a protein that acts like a glue keeping epithelial cells together. Packed between cells, it is not readily accessible. One possibility is that cell-cell junctions may open briefly as cells migrate. Another is that some other proteins may be destabilizing the barrier to provide access to E-cadherin. "We are in the process of investigating this critical point," Cossart says.
Internalin's uncompromising nature complicated the animal studies. Although the E-cadherin in humans binds internalin, those in rats and mice do not. The specificity originates from a difference of just one residue in the E-cadherins. Human E-cadherin has proline at position 16, the critical residue for binding internalin; in E-cadherins from rats and mice, glutamic acid occupies this position.
For their animal models, the researchers turned to guinea pigs, which produce E-cadherin similar to that in humans, and to engineered mice expressing human E-cadherin. They "are the first to make a transgenic mouse expressing a human receptor for a bacterial pathogen," Finlay notes in an accompanying Science commentary.
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