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A Pathogen's Wily Ways

AIDS, malaria and tuberculosis, the world¿s top three infectious killers, shimmune system, convert the cell into a microbial manufacturing plant. After multiplying, the microbes break out of the cell and go on to invade other cells, repeating the process. Details of these events have eluded investigators because such intracellular pathogens are difficult to study. As a result, researchers have yet to develop effective vaccines against them. But according to a report published in the November 3 issue of the journal Science, scientists have finally learned how one microbe, the food-borne bacterium Listeria monocytogenes (which can lead to meningitis and death), accomplishes this feat. The new findings could shed light on how other deadly pathogens operate.

Listeria bacteria, it turns out, have a remarkable mechanism for establishing infection. First they prompt immune system scavenger cells called macrophages to ingest them such that they wind up enclosed in bubbles called vacuoles inside the cells. The Listeria then make a toxin known as listeriolysin O, which is used to rupture the vacuole, gaining entry into the cell¿s interior. It subsequently coopts the cell machinery in order to replicate. What has long baffled microbiologists, though, is why the toxin doesn¿t also puncture and kill the cell. Indeed, the fact that the toxin targets the vacuole is what makes Listeria virulent. Earlier research revealed that substituting the bacteria¿s listeriolysin with a related toxin from a bacterium that operates outside of cells resulted in Listeria that broke out of the vacuole but then also bored through the cell¿s outer membrane, killing the cell. The altered strain was rendered avirulent, because the immune system was able to eliminate the exposed pathogens.

In the new study, Amy Decatur and Daniel Portnoy of the University of California at Berkeley sought to identify what makes listeriolysin so special by examining the DNA sequences of the two toxins. Their comparison revealed a key difference. The listeriolysin bears a protein tag known as a PEST sequence, which essentially tells the cell to get rid of it. Thus, before the toxin has a chance to attack the cell membrane, the cell¿s maintenance crew disposes of it. Decatur and Portnoy demonstrated the importance of the PEST tag itself by mutating it so that the cell could not recognize it. As a result, the mutant bacteria quickly destroyed the host cells, at which point the immune system launched a fatal attack against the Listeria. In the end, the wild Listeria were 10,000 times more virulent than the mutants. "It¿s a great example," remarks Portnoy, "of how bacteria have taken advantage of the host¿s biology to enhance their pathogenicity.

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