Location: Animal Parasitic Diseases LaboratoryTitle: Bacillus thuringiensis-derived Cry5B has potent anthelmintic activity against Ascaris suum) Author
Submitted to: PLOS Neglected Tropical Diseases
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/27/2013
Publication Date: 6/21/2013
Citation: Urban, Jr., J.F., Hu, Y., Miller, M.M., Scheib, U., Yiu, Y.Y., Aroian, R.V. 2013. Bacillus thuringiensis-derived Cry5B has potent anthelmintic activity against Ascaris suum. PLOS Neglected Tropical Diseases. 7(6):e2263. Interpretive Summary: Ascaris suum is an intestinal parasitic roundworm of pigs that is very closely related to Ascaris lumbricoides, a major intestinal parasitic roundworm of humans that infects more than one billion people worldwide. Because of reduced efficacy and the threat of resistance to the current small set of approved drugs to treat Ascaris infections, new treatments are needed. Here we test against A. suum infections the effectiveness of Cry5B, a roundworm-killing protein made by the natural soil bacterium Bacillus thuringiensis and representing a promising new class of anti-worm proteins (anthelmintics). We demonstrate for the first time that A. suum possesses the receptors to bind Cry5B and that Cry5B can kill A. suum juvenile larvae and adult worms in culture. Most importantly, we demonstrate that oral administration of Cry5Bto pigs infected with A. suum larvae results in a near complete elimination of the infection from the intestine. Given the similarities between A. suum and A. lumbricoides and the similarity between the pig and human gastrointestinal tracts, our data indicate that Cry5B has excellent potential to treat Ascaris infections in veterinary animals and in humans. This information will be important to scientists that study the control of parasite infections in animals and humans, and to swine producers as a potential new source of compounds to eliminate roundworm infections in their animals.
Technical Abstract: Ascaris suum and Ascaris lumbricoides are two closely related geo-helminth parasites that ubiquitously infect pigs and humans, respectively. Ascaris suum infection in pigs is considered a good model for A. lumbricoides infection in humans because of a similar biology and tissue migration to the intestines. Ascaris lumbricoides infections in children are associated with malnutrition, growth and cognitive stunting, immune defects, and, in extreme cases, life threatening blockage of the digestive tract and aberrant migration into the bile duct and peritoneum. Similar effects can be seen with A. suum infections in pigs related to poor feed efficiency and performance. New strategies to control Ascaris infections are needed largely due to reduced treatment efficacies of current anthelmintics in the field, the threat of resistance development, and the general lack of new drug development for intestinal soil transmitted helminths for humans and animals. Here we demonstrate for the first time that A. suum expresses the receptors for Bacillus thuringiensis crystal protein and novel anthelmintic Cry5B, which has been previously shown to intoxicate hookworms and which belongs to a class of proteins considered non-toxic to vertebrates. Cry5B is able to intoxicate A. suum larvae and adults and triggers the activation of the p38 mitogen-activated protein kinase pathway similar to that observed with other roundworms. Most importantly, two moderate doses of 20 mg/kg body weight (143 nM/kg) of Cry5B resulted in a near complete cure of intestinal A. suum infections in pigs. Taken together, these results demonstrate the excellent potential of Cry5B to treat Ascaris infections in pigs and in humans and for Cry5B to work effectively in the human gastrointestinal tract.