A family of receptors that enable disease-causing toxins produced by the bacterium Clostridium difficile to enter host cells in mice is identified in a study published in Nature this week. These findings may help pinpoint potential therapeutic targets for treating diseases associated with C. difficile, such as gastroenteritis.
Infection of the colon with bacterium C. difficile is a leading cause of gastroenteritis-associated death in developed countries, accounting for 29,000 deaths annually in the United States and nearly half- a million cases of diarrhoea. Although it is known that two toxins - toxin A and toxin B - are the causal agents for diseases associated with C. difficile infection, exactly how toxin B targets the cells lining the colon (epithelium) has been unclear.
Min Dong and colleagues use a genome-wide CRISPR/Cas9-mediated screen to identify members of the Frizzled family of Wnt receptors as receptors for toxin B in model organoids of the colon and in the epithelium of the colon in mice. They show that the Wnt receptor allows the toxin to enter host cells. The authors also show that genetic deletion of the Frizzled family of receptors results in increased resistance to toxin B in mouse model organoids and decreased susceptibility to toxin-B-induced colonic tissue damage in live mice.
These findings establish Frizzled family receptors as disease-relevant receptors for toxin B in the colonic epithelium and provide novel therapeutic targets for treating C. difficile infections.