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MICROBIOLOGY
Cholera Bacteria Break from Biofilm to Cause DiseaseFindings on Quorum Sensing Suggest New Model of Pathogenic CycleBacteria, like animals, appear to seek sufficient numbers to accomplish the tasks they cannot do alone. The Vibrio cholerae species of bacteria aggregate into protective biofilms in the ocean, for example, and these defensive clusters may help them weather the stomach acid they encounter when humans ingest them through contaminated water or food. But unlike most pathogenic bugs, cholera bacteria may go on the offensive as lone wolves, breaking away from the pack to establish new territory in the gut.
A new model of the infectious cycle of V. cholerae makes sense of unexpected findings about their quorum-sensing behavior. Quorum-sensing works at two stages, propose Jun Zhu and John Mekalanos, first to limit the protective biofilm so they can survive the stomach but break away in the gut, and then to break away from the gut and back into the environment. According to a study in the October 2003 Developmental Cell, quorum sensing results in this breakdown of cholera's biofilm communities, freeing the bugs in the small intestines where they do more damage as individual cells. This stage apparently is the second point in their pathogenic cycle that the bacteria rely on quorum sensing. After the bugs multiply, their genetic circuits for monitoring their population density lead to the deactivation of their virulence factors, helping the bacteria exit the gut. "Quorum sensing has to work twice," said senior author John Mekalanos, the Adele Lehman professor of microbiology and molecular genetics at HMS and chair of that department. "Once they pass through the stomach acid, V. cholerae have to exit the biofilm and become free-living cells," he said. "Once they are free living, they initiate colonization and replication and growth. They won't get to the quorum-sensing state again until they fully colonize the host." This new model of the infectious cycle of cholera is based on findings about the bacteria's unexpected group behavior by Mekalanos, HMS postdoctoral fellow Jun Zhu, and their colleagues. Group HugsLast year, Zhu reported the first surprising news: with lots of their own kind around them, cholera bacteria become mild mannered and repress expression of their virulence factors. The paper was published in the March 5, 2002 Proceedings of the National Academy of Sciences."Our focus was on why quorum sensing is important for V. cholerae pathogenesis," Zhu said. Before joining the Mekalanos lab, he studied quorum-sensing bacteria as a graduate student with Cornell University microbiologist Stephen Winans. (About 10 years ago, Winans's brother-in-law, a lawyer, first named the phenomenon "quorum sensing" after Winans explained his research at a family Thanksgiving feast.) Doing It My WayNow, in their most recent paper, Zhu and Mekalanos report that cholera's quorum-sensing system also suppresses biofilm formation. At the molecular level, the signal transduction pathway turns off the Vibrio polysaccharide synthesis (vps) operons that make the sticky matrix for biofilms. Quorum sensing also triggers a protease known to detach cells, perhaps both from the epithelial lining of the intestine and from biofilm aggregations. "Quorum sensing lets the bacteria leave the biofilm at the right time to find new opportunities after infection," Zhu said.
Jun Zhu (left) and John Mekalanos propose a new model about the infectious cycle of cholera bacteria based on new findings about their behavior changes in a V. cholerae crowd. (Photo by Graham Ramsay) In test tubes, V. cholerae biofilms were at least 1,000 times more resistant to acid shock than free-living cells, but bigger is not necessarily better when it comes to V. cholerae biofilm communities. The thinner wild-type biofilm protected the bacteria from acid just as well as a thicker mutant biofilm. Mice were 10 times less likely to get sick from the thicker mutant biofilms than from the thinner wild-type groupings. At some point, cholera bacteria need to escape from the biofilm to cause disease. "In the aquatic environment, this may be the way to move on to better locations, for example, after the death of their host when the plankton bloom 'crashes,'" said Rita Colwell, distinguished university professor of microbiology and molecular biology at the University of Maryland, College Park, and director of the National Science Foundation. "The bacterium is an environmental cowboy, riding its plankton hosts, with human disease an unintended consequence. The model dovetails nicely with our research on the climate-cholera epidemic relationship and also on the work we have done showing that V. cholerae attached to plankton and particulates can be effectively filtered out of water using a simple sari cloth folded four to eight times." The model also makes sense to Bonnie Bassler, professor of molecular biology at Princeton, who studies cell-to-cell communication in bacteria. Bassler's group collaborated with Zhu and Mekalanos on the PNAS paper last year. In parallel follow-up work, Bassler's group also found that quorum sensing squelches cholera biofilm formation by turning off polysaccharide production at high cell density. --Carol Cruzan Morton |
