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Sep 11, 2013

New Insight on How Cholera Kills

  • Scientists at the University of California-San Diego say they have uncovered a biochemical mechanism that helps make cholera toxin (CT) so deadly. Individuals afflicted with the disease often suffer life-threating diarrhea that causes them to lose as much as half of their body fluids in a single day.

    Studying fruit flies, mice, and cultured human intestinal cells, researchers looked at cholera toxin, which is produced by Vibrio cholerae. They discovered that the enzymatic form of CT (CtxA) severely reduces the delivery of proteins to molecular junctions that normally act to hold intestinal cells together in the outer lining of the gut.

    “We find that CtxA-driven cAMP increase inhibits Rab11/exocyst-mediated trafficking of host proteins including E-cadherin and Notch signaling components to cell-cell junctions in Drosophila, human intestinal epithelial cells, and ligated mouse ileal loops, thereby disrupting barrier function,” wrote the researchers in the September 11 issue of Cell Host and Microbe. “Additionally, CtxA induces junctional damage, weight loss, and dye leakage in the Drosophila gut, contributing to lethality from live V. cholerae infection, all of which can be rescued by Rab11 overexpression.”

    “A consequence of these weakened cell junctions is that sodium ions and water can escape between cells and empty into the gut,” explained Ethan Bier, Ph.D., a professor of biology at UC San Diego, who headed one of the two teams involved in the scientific investigation.

    Dr. Bier and his team believe their findings could guide the development of new therapies against the deadly disease, which threatens millions of people in poor countries around the world.

    The study built on research published decades ago, when scientists discovered that cholera toxin caused the overproduction of small chemical messenger molecule cyclic adenosine monophosphate, or “cAMP,” in epithelial cells lining the intestine.

    “High levels of cAMP activate a protein channel called CFTR that allows the negatively charged chloride ions to rush out of intestinal epithelial cells into the contents of the gut,” said Victor Nizet, M.D., a professor of pediatrics and pharmacy at UC San Diego School of Medicine, who headed the other team. “Through basic physiological principals known as electroneutrality and osmotic balance, these secreted chloride ions must be accompanied by positively charged sodium ions and water, altogether leading to a profuse loss of salt and water in the diarrheal stools.”

    The molecular mechanism by which this massive flux of sodium and water into the gut occurs as a result of the cholera toxin remained a mystery until Annabel Guichard, Ph.D., a research scientist working in Dr. Bier’s laboratory and the lead author of the paper, began conducting experiments that spearheaded the two groups’ collaboration.

    The UC San Diego researchers found that cholera toxin acts by two entirely distinct but cooperating mechanisms to produce diarrhea. In addition to increasing the efflux of chloride ions through the CFTR channel, it weakens cell junctions to allow a rapid outflow of counterbalancing sodium ions and water between the cells. The scientists showed that many of the effects of the cholera toxin on the gut could be reversed by genetic manipulations that bolster the delivery of proteins to these junctions.

    “Determining how the various effects of cAMP overproduction are integrated to alter barrier integrity and assessing the full contribution of the junctional defects we describe here to the pathogenesis of cholera are important lines of inquiry for future studies,” concluded the scientists in their journal article (“Cholera Toxin Disrupts Barrier Function by Inhibiting Exocyst-Mediated Trafficking of Host Proteins to Intestinal Cell Junctions”).

    Understanding this novel mechanism of cholera action could also have important implications for other disorders of intestinal barrier function such as Crohn’s disease, colitis, and celiac disease, according to the researchers.

    “The development of drugs that mimic the genetic manipulations performed in our study may help restore integrity to a damaged intestinal barrier,” noted Dr. Guichard. “This new approach could reduce disease symptoms in cholera and other chronic gut disorders.”



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