A joint team from the University of California, Irvine (UCI) and Harvard University have found out how Clostridium difficile toxin B (TcdB) recognizes and uses the human Frizzled protein receptor to invade intestinal cells and cause gastrointestinal infections. Their work was published last week in Science and could also help develop new cancer drugs.
In a C. diff infection, TcdB targets the colonic epithelia and binds to Frizzled (FZD) receptors. The researchers found that when binding, the toxin locks certain lipid molecules in FZD, which then block the Wnt signaling that regulates the renewal of colonic stem cells and the differentiation of the epithelium in the colon.
"This toxin is indeed very smart. It takes advantage of an important lipid that FZD uses for its own function, to improve its binding affinity and specificity to FZD," said co-corresponding author Rongsheng Jin. "However, the need for this lipid also exposes a vulnerability of TcdB that could be exploited to develop antitoxins that block toxin-receptor recognition."
Co-corresponding author Min Dong and Jin believe that the mechanism used by toxin B could actually turn the deadly toxin into an anti-cancer drug. Their preliminary data so far shows that the non-toxic fragment of TcdB could inhibit the growth of cancer cells since it interrupts Wnt signaling.
The findings are promising and it would be amazing to see this dangerous toxin be turned against cancer.
Image: Clostridium difficile (C. diff) causes severe gastrointestinal tract infections. The 3-D structure shows how a key C. diff toxin, TcdB (in orange), recognizes the human Frizzled protein (in green) as its receptor to invade cells, leading to damage in the intestinal barrier. Shown in the background is immunofluorescent staining of the healthy mouse cecum tissue (left) and the one damaged by TcdB (right). Image courtesy of Rongsheng Jin from the University of California, Irvine.