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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.    Methodology/Principal Findings  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/Significance  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.

Mechanistic and Single-Dose In Vivo Therapeutic Studies of Cry5B Anthelmintic Action against Hookworms