title: Mechanistic and single-dose in vivo therapeutic studies of Cry5B anthelmintic action against hookworms.
abstract: BACKGROUND
  Hookworm infections are one of the most important parasitic infections of humans worldwide, considered by some second only to malaria in associated disease burden. Single-dose mass drug administration for soil-transmitted helminths, including hookworms, relies primarily on albendazole, which has variable efficacy. New and better hookworm therapies are urgently needed. Bacillus thuringiensis crystal protein Cry5B has potential as a novel anthelmintic and has been extensively studied in the roundworm Caenorhabditis elegans. Here, we ask whether single-dose Cry5B can provide therapy against a hookworm infection and whether C. elegans mechanism-of-action studies are relevant to hookworms.
  
  
  RESULTS
  To test whether the C. elegans invertebrate-specific glycolipid receptor for Cry5B is relevant in hookworms, we fed Ancylostoma ceylanicum hookworm adults Cry5B with and without galactose, an inhibitor of Cry5B-C. elegans glycolipid interactions. As with C. elegans, galactose inhibits Cry5B toxicity in A. ceylanicum. Furthermore, p38 mitogen-activated protein kinase (MAPK), which controls one of the most important Cry5B signal transduction responses in C. elegans, is functionally operational in hookworms. A. ceylanicum hookworms treated with Cry5B up-regulate p38 MAPK and knock down of p38 MAPK activity in hookworms results in hypersensitivity of A. ceylanicum adults to Cry5B attack. Single-dose Cry5B is able to reduce by >90% A. ceylanicum hookworm burdens from infected hamsters, in the process eliminating hookworm egg shedding in feces and protecting infected hamsters from blood loss. Anthelmintic activity is increased about 3-fold, eliminating >97% of the parasites with a single 3 mg dose (∼30 mg/kg), by incorporating a simple formulation to help prevent digestion in the acidic stomach of the host mammal.
  
  
  CONCLUSIONS
  These studies advance the development of Cry5B protein as a potent, safe single-dose anthelmintic for hookworm therapy and make available the information of how Cry5B functions in C. elegans in order to study and improve Cry5B function against hookworms.
authors.affiliation: Section of Cell and Developmental Biology, University of California San Diego, La Jolla, California, United States of America. bzhan@bcm.edu
authors.forename: Yan
authors.initials: Y
authors.lastname: Hu
authors.forename: Bin
authors.initials: B
authors.lastname: Zhan
authors.forename: Brian
authors.initials: B
authors.lastname: Keegan
authors.forename: Ying Y
authors.initials: YY
authors.lastname: Yiu
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Miller
authors.forename: Kathryn
authors.initials: K
authors.lastname: Jones
authors.forename: Raffi V
authors.initials: RV
authors.lastname: Aroian
mesh_terms: D000722:Ancylostoma / Q000187:drug effects*; D000724:Ancylostomiasis / Q000188:drug therapy*; D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage*; D000083722:Bacillus thuringiensis Toxins; D001426:Bacterial Proteins / Q000008:administration & dosage*; D006224:Cricetinae; D004195:Disease Models, Animal; D004731:Endotoxins / Q000008:administration & dosage*; D005243:Feces / Q000469:parasitology; D005260:Female; D006460:Hemolysin Proteins / Q000008:administration & dosage*; D008297:Male; D008647:Mesocricetus; D010270:Parasite Egg Count; D016896:Treatment Outcome
chemical_list: D000871:Anthelmintics; D000083722:Bacillus thuringiensis Toxins; D001426:Bacterial Proteins; D004731:Endotoxins; D006460:Hemolysin Proteins; C030956:insecticidal crystal protein, Bacillus Thuringiensis