: Bacillus thuringiensis (Bt) crystal (Cry) proteins have been used for decades to kill insect pests, including mosquitoes and black flies that transmit human diseases. Cry proteins related to those that kill insects have now been discovered to kill nematodes, although they are not currently used for nematode control. Cry proteins are non-toxic to mammals, making them excellent choices as insecticides and potentially as nematicides. Nematicidal Cry proteins intoxicate a wide range of nematodes, including C. elegans and two mammalian parasitic nematodes that infect the intestine. Intestinal nematodes infect over 1/4 of the human population making them an important medical target for Cry proteins. This application proposes to take advantage of the excellent tools available with C. elegans to study in depth how Cry proteins function, how resistance to Cry proteins develop (an important question even for insects), and, for the first time, address whether Cry proteins have utility in controlling mammalian parasitic nematodes. Variants of one Cry protein with better toxicity towards nematodes will be evolved and then tested for altered functions to correlate structure of toxin with function of toxin (Specific Aim I). This application also proposes to explore the mechanism of resistance to a different nematicidal Cry protein in C. elegans and determine whether this nematicidal protein may be an excellent companion therapeutic for other Cry proteins (Specific Aim II). The information and Cry protein variants generated and studied in Specific Aims I and II will then be applied towards therapy of mammalian parasites. Cry proteins, wild type and improved variants, will be orally administered to rodents infected with intestinal parasites (including one that can infect humans) to optimize therapeutic regimens and to determine which Cry proteins can have a therapeutic effect against the nematodes. The goal of these trials is to lay a foundation for future human studies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-TMP (99))
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Coyne, Philip Edward
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University of California San Diego
Schools of Arts and Sciences
La Jolla
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Tyagi, Rahul; Maddirala, Amarendar Reddy; Elfawal, Mostafa et al. (2018) Small Molecule Inhibitors of Metabolic Enzymes Repurposed as a New Class of Anthelmintics. ACS Infect Dis 4:1130-1145
Hu, Yan; Nguyen, Thanh-Thanh; Lee, Alice C Y et al. (2018) Bacillus thuringiensis Cry5B protein as a new pan-hookworm cure. Int J Parasitol Drugs Drug Resist 8:287-294
Papaiakovou, Marina; Pilotte, Nils; Baumer, Ben et al. (2018) A comparative analysis of preservation techniques for the optimal molecular detection of hookworm DNA in a human fecal specimen. PLoS Negl Trop Dis 12:e0006130
Chen, Huan-Da; Kao, Cheng-Yuan; Liu, Bang-Yu et al. (2017) HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans. Autophagy 13:371-385
Noon, Jason B; Aroian, Raffi V (2017) Recombinant subunit vaccines for soil-transmitted helminths. Parasitology 144:1845-1870
Dementiev, Alexey; Board, Jason; Sitaram, Anand et al. (2016) The pesticidal Cry6Aa toxin from Bacillus thuringiensis is structurally similar to HlyE-family alpha pore-forming toxins. BMC Biol 14:71
Durmaz, Evelyn; Hu, Yan; Aroian, Raffi V et al. (2016) Intracellular and Extracellular Expression of Bacillus thuringiensis Crystal Protein Cry5B in Lactococcus lactis for Use as an Anthelminthic. Appl Environ Microbiol 82:1286-94
Schwarz, Erich M; Hu, Yan; Antoshechkin, Igor et al. (2015) The genome and transcriptome of the zoonotic hookworm Ancylostoma ceylanicum identify infection-specific gene families. Nat Genet 47:416-22
Wu, Chia-Chen; Hu, Yan; Miller, Melanie et al. (2015) Protection and Delivery of Anthelmintic Protein Cry5B to Nematodes Using Mesoporous Silicon Particles. ACS Nano 9:6158-67
Somvanshi, Vishal S; Ellis, Brian L; Hu, Yan et al. (2014) Nitazoxanide: nematicidal mode of action and drug combination studies. Mol Biochem Parasitol 193:1-8

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