An inactivated bacterium (paraprobiotic) expressing Bacillus thuringiensis Cry5B as a therapeutic for Ascaris and Parascaris spp. infections in large animals

Authors: Urban, Joseph; NIELSEN, MARTIN - University Of Massachusetts; GAZZOLA, DAVID - University Of Massachusetts; XIE, YUE - Non ARS Employee; Beshah, Ethiopia; HU, YAN - University Of Massachusetts; RUS, FLORENTINA - University Of Massachusetts; FLANAGAN, KELLY - University Of Massachusetts; DRAPER, AUSTIN - Utah State University; VAKALAPUDI, SRIDHAR - Utah State University; Li, Robert; OSTROFF, GARY - University Of Massachusetts; AROIAN, RAFFI - University Of Massachusetts

Submitted to: Elsevier
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/22/2020
Publication Date: 7/22/2020
Citation: Urban Jr, J.F., Nielsen, M., Gazzola, D., Xie, Y., Beshah, E., Hu, Y., Rus, F., Flanagan, K., Draper, A., Vakalapudi, S., Li, R.W., Ostroff, G.R., Aroian, R.V. 2020. An inactivated bacterium (paraprobiotic) expressing Bacillus thuringiensis Cry5B as a therapeutic for Ascaris and Parascaris spp. infections in large animals. Elsevier. 164:994-1005. https://doi.org/10.1016/j.onehlt.2021.100241.
DOI: https://doi.org/10.1016/j.onehlt.2021.100241

Interpretive Summary: Parasitic nematodes (worms) that infect livestock reduce production of meat, milk, fiber and compromise health. They also have deleterious effects on the health of humans in areas of the world were these infections are common. Two large intestinal parasitic worms that commonly infect pigs (Ascaris suum) and horses (Parascaris spp) are very similar to Ascaris lumbriocoides that infects over a billion people worldwide. Studies of these worms in livestock have inherent interest for enhancing the health of these animals but also as the results can be applied to humans under the concept of "One Health" that examines common features of infections in animals and humans. For example, Ascaris is zoonotic which means it is able to pass from humans to pigs and vice versa. The development of new therapies to control these parasites would have major benefits for both human and livestock health. Here we tested the therapeutic ability of a paraprobiotic or dead probiotic that expresses a crystal protein (Cry5B) derived from soil bacteria that has been demonstrated in the laboratory to have anti-parasitic properties against parasites in mice and when tested in cultures of growing parasites. In this study, the paraprobiotic was scaled up to large volumes to treat pigs and horses. A single dose of this Cry5B containing paraprobiotic nearly cleared all A. suum infections in pigs and also significantly reduced infection of young horses with Parascaris; which is superior to all currently used drugs against this parasite. This represents a new paraprobiotic compatible with the concept of One Health that is safe, effective, massively scalable, stable, and useful in human and veterinary medicine in both the developed and developing worlds.

Technical Abstract: Ascaris and Parascaris are important parasites in the family Ascarididae, large, ubiquitous intestinal-dwelling nematodes infecting all classes of vertebrates. Parasitic nematode drug resistance in veterinary medicine and drug recalcitrance in human medicine are increasing worldwide, with few if any new therapeutic classes on the horizon. Some of these parasites are zoonotic, e.g., Ascaris is able to pass from humans to pigs and vice versa. The development of new therapies against this family of parasites would have major implications for both human and livestock health. Here we tested the therapeutic ability of a paraprobiotic or dead probiotic that expresses the Bacillus thuringiensis Cry5B protein with known anthelmintic properties, against zoonotic Ascaris suum and Parascaris spp. This paraprobiotic, known as IBaCC, intoxicated A. suum larvae in vitro and was highly effective in vivo against intestinal A. suum infections in a new mouse model for this parasite. Fermentation was scaled up to 30 liters to treat pigs and horses. Single dose Cry5B IBaCC nearly completely cleared A. suum infections in pigs. Furthermore, single dose Cry5B IBaCC drove fecal egg counts in Parascaris-infected foals to zero, showing superiority to all currently used drugs against this parasite. Cry5B IBaCC therefore represents a new, paraprobiotic One Health approach towards targeting Ascarididae that is safe, effective, massively scalable, stable, and useful in human and veterinary medicine in both the developed and developing worlds.