Their discovery, detailed in this week’s early online edition of the Proceedings of the National Academy of Sciences, could pave the way for the development of more effective treatments for hookworm and other soil-transmitted nematode infections, which are a major global health problem in developing countries. Many of the nearly two billion people worldwide infected with these intestinal parasites are children, who are at particular risk for anemia, malnutrition and delayed growth.
The UCSD-Yale team found that a protein produced by the bacterium Bacillus thuringiensis, or Bt, given orally to laboratory hamsters infected with hookworms was as effective in eliminating the parasites, curing anemia and restoring weight gain in the hamsters as mebendazole, one of the drugs currently recommended to treat infections in humans. The scientists also discovered that this protein, called Cry5B, targets both developing, or larval, stages and adult parasites, as well as impairs the excretion of eggs by female worms.
Hookworms cause anemia by attaching to the intestine and feeding on their host’s blood and nutrients, causing anemia and weight loss. The researchers said in their paper that because this naturally-produced 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, one of two principal authors of the study and a 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.”
The discovery is particularly relevant to global health, because of concerns about the potential emergence of resistance in human intestinal nematodes to currently available medicines.
“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 and co-principal author of the study. " 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.”
Other authors of the study are Richard Bungiro and Lisa Harrison of the Yale medical school and Larry Bischof, Joel Griffitts and Brad Barrows of UCSD.
Aroian and his UCSD colleagues discovered five years ago that the roundworm C. elegans and other nematodes are susceptible to the effects of Cry5B, then known primarily as an insecticide. The toxin forms tiny holes in the membranes of the cells of nematodes and insects. However, since the toxin can’t bind to the cells of mammals or other vertebrates, Cry proteins 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.”
Aroian met Cappello, a pediatric infectious diseases specialist who studies hookworm, at a meeting of the Burroughs-Wellcome Fund and decided to collaborate on a project to see if crystal proteins could be effective against hookworm infections. Three years ago, Aroian and his colleagues purified Cry5B toxin and sent it to Cappello, who then tested the compound in a laboratory model of hookworm infection.
“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.”
Colleagues in Cappello’s lab then carried out additional experiments that demonstrated that Cry5B was comparable to mebendazole for treating hookworm infection in laboratory animals. Additional studies also determined which life cycle stages of the parasite were most susceptible to Cry5B and at what concentrations.
“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.”
The study was supported by grants from the National Institutes of Health and the Burroughs Wellcome Fund.
Kim McDonald | EurekAlert!
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy