Proteins in soil bacteria could help fight worms
A protein made by common soil bacteria may help treat a parasitic problem common in ruminants, according to a recent study.
A related study also indicates that the substance is highly toxic to a hookworm that parasitizes humans. But any commercial product, in veterinary or human medicine, will likely stick around for years to come.
An article published in November in the International Journal of Parasitology: Drugs and Drug Resistance describes promising results for a Haemonchus contortus treatment in sheep that uses crystal proteins contained in the cell walls of Bacillus thuringiensis bacteria. In the digestive system of a ruminant, H contortion ingests dead bacteria containing crystal proteins, which bind to the intestinal cells of the nematode and kill the nematode.
Joseph F. Urban Jr., PhD, supervising microbiologist for the Agricultural Research Service of the U.S. Department of Agriculture, was among contributors to studies involving H contortion and human parasitic hookworm Ancylostoma ceylanicum. He described the results as the most encouraging he has seen since the development of ivermectin.
Dr Urban noted that similar crystalline lysate powders have been used as insecticides in agriculture for decades, and home gardeners sprinkle their tomatoes with these products. Some transgenic food crops are modified to produce crystal proteins, he said.
The study involving H contortion in ruminants was a collaboration between researchers at the USDA Agricultural Research Service, University of Massachusetts, Virginia-Maryland College of Veterinary Medicine, University of California-San Diego, Worcester State University, Utah State University and the University of Rhode Island. A USDA announcement says the experimental treatment resulted in dramatic reductions in parasites in infected sheep with no damage observed to the sheep.
Dr Ray M. Kaplan, professor of parasitology at the College of Veterinary Medicine at the University of Georgia, said crystal protein products show promise, but probably years away from their availability due to the need to continue. research on aspects such as dosage and administration. If they become available, farmers and veterinarians will need to treat them with care and incorporate them into pest management plans that include complementary management. Otherwise, selection for drug resistance could reduce the effectiveness of these products, as happened with approved anthelmintics, he said.
Dr Kaplan has collaborated on ongoing studies using the same crystal proteins to treat hookworms in dogs, with encouraging results so far.
Cry5B and IBaCC
The International Journal of Parasitology article indicates that researchers experimentally infected goats and sheep with H contortion and administered to each species a different treatment in oral suspension. The two treatment substances were forms of B thuringiensis crystal protein 5B, abbreviated as Cry5B. B thuringiensis naturally releases crystals at the same time as it releases spores.
Researchers tested this natural form of Cry5B in goats and found no effect on H contortion. But the research team found that Cry5B may become an effective anthelmintic against H contortion larvae in sheep when the B thuringiensis are killed and the crystals remain contained in the cell walls of dead bacteria.
This active pharmaceutical ingredient is named IBaCC – inactivated bacterium with cytosolic crystal.
Sheep given IBaCC had a 72% lower parasite load compared to experimentally infected controls, and their fecal egg count dropped from 88% to 96%. The study authors attributed the larger drop in egg numbers to a 96% reduction in female worms, compared to a 60% reduction in males.
Raffi V. Aroian, PhD, professor of molecular medicine at UMass Medical School and one of the principal investigators for studies on H contortion and A ceylanic, suspects that the different formulations explain most of the differences in results between sheep and goats, and the International Journal of Parasitology article suggests that the IBaCC version may keep more crystal protein intact in the rumen before it does. they do not enter the abomasum. The article also states that the differences may be related to factors such as the higher volumes and number of doses given to sheep and the differences between the sheep and the goats themselves.
But Dr Aroian said that an as yet unpublished study shows that, contrary to statements in the International Journal of Parasitology article, smaller doses of IBaCC in sheep were effective against H contortion.
A scientific paper published in December 2020 in Antimicrobial Agents and Chemotherapy — written by some of the same researchers as the H contortion article – describes the development of IBaCC and indicates that IBaCC has been effective in killing human parasites A ceylanic hookworms in tests using hamsters. The article states that crystal proteins are considered non-toxic to vertebrates, even in high doses, and that people have been using crystal proteins for over 60 years to control populations of caterpillars, beetles, black flies and blackflies. mosquitoes.
“The IBaCC promises new hope for a new arsenal of anthelmintics against the most common parasites in humans and animals,” the article says.
Widespread resistance to existing drugs
Dr Dante Zarlenga, a microbiologist at the ARS Animal and Parasitic Diseases Laboratory and one of the co-authors of the International Journal of Parasitology article, said in a post that drug resistance H contortion is present in almost every sheep and goat farm in the United States, and farm parasites are particularly resistant to ivermectin and its derivatives. Dr Zarlenga also expressed doubt that anyone was conducting large-scale studies or surveillance of parasite levels, parasite species and drug resistance.
Dr Kaplan said Haemonchus nematodes are ubiquitous, and he doubts whether a sheep or goat can make it through the hot months of the year on an American pasture without being infected. He is in the process of finalizing a manuscript on a retrospective study of the prevalence of resistance over the period 2000-16 on hundreds of farms.
Dr Kaplan said his data indicates that most farms appear to be reduced to a well-working anthelmintic drug, and some have none. The problem is worse in the eastern United States, he said.
Dr Kaplan suspects that the parasites would develop resistance to Cry5B more slowly than to existing anthelmintics, because it kills the worms by a different mechanism of action than existing drugs. But he expects widespread use can speed up this selection process.
He warned that vets and farmers have yet to move away from the idea that they can eliminate parasites with pharmaceuticals and recognize that parasites need management that includes back-up methods. These include implementing the concept of refuge to leave some animals untreated, reducing drug treatments, monitoring pasture height and forage quality, maintaining lower stocking densities and adding, for example, plants rich in tannins or copper to the diet of ruminants.
Even with a new class of anthelmintics, Dr Kaplan doubts farmers will see another era where monthly dewormers alone will give them healthy, fast-growing, high-density herds.
Dr Anne Zajac, professor of parasitology at Virginia-Maryland who was among the authors of articles in the International Journal of Parasitology, said studies conducted so far on crystal proteins have shown the product’s activity against parasitic nematodes, and further studies will help determine the best doses. and formulas. Next steps towards Food and Drug Administration approval include toxicology studies, although she said no studies have shown toxic effects of crystal proteins on vertebrates.
Dr Zajac expects that existing knowledge on how to produce crystal proteins as insecticides will facilitate the production of products similar to those of commercial anthelmintics. Because Cry5B is a member of a family of crystal proteins under study, she expects that current studies may produce several related products, some of which may be more effective than Cry5B.
Dr Aroian said his lab is testing at least half a dozen crystal proteins to verify their effectiveness, although Cry5B is the most advanced. He and Gary Ostroff, PhD, professor at UMass Medical School, plan to develop the products for humans and livestock in parallel investigations, and he wants to start working with the FDA to obtain the necessary approvals to de new clinical studies. He is looking for business partners, and he sees a need for the product among sheep farmers in particular.
“We are really here to make a difference in helping people cope with these parasites, and we believe that goes for humans and for livestock,” said Dr Aroian. “This thing has huge potential to really help.”