Bacterial Toxin Used as Insecticide Kills Intestinal Worms

A toxic protein produced by Bacillus thuringiensis (Bt), a bacterium used against crop pest insects, has been discovered as highly effective in the treatment of hookworm (photo) infections.

Hookworms attach to the intestine and feed on their host’s blood and nutrients, causing anemia and weight loss. This finding could help the development of drugs with no secondary effects in the treatments for hookworm and other soil-transmitted nematode infections or intestinal worms, which are a major health problem in developing countries.

Nearly two billion people are infected with these intestinal parasites, and many are children, who are at particular risk for anemia and delayed growth.

The protein, called Cry5B, given orally to laboratory hamsters infected with hookworms, eliminated the parasites, curing anemia and restoring weight gain in the hamsters at the same level as mebendazole, one of the drugs currently used to treat infections in humans.

The protein kills both larval stages and adults and impairs the release of eggs by females. Because this protein is safe to humans and other vertebrates and can be produced inexpensively in large quantities, it has the potential to substantially improve this global health problem.

"Our ability to control parasitic nematode infections with chemotherapy on a global scale is dependent on the availability of medicines that are safe, effective, and inexpensive to manufacture," said Michael Cappello, professor of pediatrics and epidemiology & public health at Yale School of Medicine.

"We believe that Bt crystal proteins not only meet, but exceed these essential criteria."

There already are concerns about the potential emergence of resistance in human intestinal nematodes to currently available drugs. "There are only a few new agents under development for the treatment of hookworm and other intestinal parasite infections," said Raffi Aroian, an associate professor of biology at UCSD.

"Crystal toxins are safe to humans, mammals and other vertebrates. And it might be possible to improve the efficacy of current treatments by giving a drug like mebendazole and Cry5B simultaneously."

Aroian discovered five years ago that the roundworm C. elegans and other nematodes are killed by Cry5B, previously used only as an insecticide. Round worms, depending on species, provoke diseases like: enterobiasis, ascariasis, trichuriasis.

The toxin forms tiny holes in the cellular membranes of the gut cells of nematodes and insects. But the protein can’t bind to the intestinal cells of mammals or other vertebrates and can’t hurt humans. "Crystal proteins had been used for decades to kill insects by organic farmers who sprayed their crops with Bt," said Aroian.

"Until now, however, no one has used a purified Cry protein to treat a parasitic nematode."

The scientists tasted the toxin in hookworms three years ago. "It worked on the first day," said Aroian. "Laboratory animals treated with Cry5B survived a lethal hookworm infection, and showed no side effects from the medication."

"These experiments confirmed that the mechanism of action of Cry5B in Ancylostoma hookworms appears to be identical to that for other nematodes, including C. elegans," said Cappello.

"This suggests that crystal proteins will likely have activity against a broad range of nematodes, and could be used to treat children who are often infected with multiple intestinal parasites. Studies are underway to fully define the spectrum of activity of Cry5B as part of its preclinical development as a human therapeutic."