In 1993, Escherichia coli, a normally harmless bacterium, drew national headlines when it sickened and killed people who ate undercooked hamburgers from a Seattle fast-food joint.
Unlike most E. coli, the strain at fault, known as O157:H7, produces two chemicals called verotoxins that destroy cells in the intestines and kidneys.
In the July 15 Genes & Development, researchers in Japan report that verotoxin II binds to a protein whose usual role is to prevent cells from committing suicide. The toxin likely kills cells by shutting down the activity of this protein, known as Bcl-2, says study coauthor Atsushi Suzuki of Daiichi Pharmaceutical Co. in Tokyo.
Although verotoxin I kills cells more efficiently in test-tube experiments than verotoxin II does, studies of people sickened by O157:H7 suggest that the second verotoxin causes most of their symptoms. Other scientists have found evidence that verotoxin I kills cells by suppressing their ability to make proteins, but how verotoxin II acts has remained unclear.
Suzuki’s team initially noticed that verotoxin II has a string of five amino acids identical to a segment in Bcl-2. The investigators then found that verotoxin II, but not the other toxin, can bind directly to Bcl-2 through this shared sequence.
Verotoxin II doesn’t trigger cell death in cells lacking Bcl-2, the researchers found. Moreover, they could limit the toxin-induced death of cells making Bcl-2 if they pretreated those cells with a protein fragment consisting of the shared amino acid sequence. It presumably prevented verotoxin II from gaining access to Bcl-2, the researchers say.
It’s still not clear how a marriage of verotoxin II to Bcl-2 induces cell death or if compounds that prevent this union will help people infected with O157:H7. Tests in animals may answer the latter question, says Suzuki, and determine whether Daiichi Pharmaceutical will try to develop a drug for this deadly form of food poisoning.
The binding of verotoxin II to Bcl-2 is a “novel and quite exciting observation,” says Clifford A. Lingwood of the Hospital for Sick Children in Toronto and the University of Toronto. “It’s an important finding that there’s an additional mechanism of killing.”
Lingwood, who’s found that verotoxins can destroy cancer cells, adds that he wouldn’t be surprised if future research uncovers other means by which these bacterial toxins kill cells. By the end of the year, his group plans to begin evaluating whether verotoxins can rid people of brain tumors.