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A Purified Bacillus Thuringiensis Crystal Protein with Therapeutic Activity Against the Hookworm Parasite Ancylostoma Ceylanicum

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A Purified Bacillus Thuringiensis Crystal Protein with Therapeutic Activity Against the Hookworm Parasite Ancylostoma Ceylanicum A purified Bacillus thuringiensis crystal protein with therapeutic activity against the hookworm parasite Ancylostoma ceylanicum Michael Cappello*†, Richard D. Bungiro*, Lisa M. Harrison*, Larry J. Bischof ‡, Joel S. Griffitts‡, Brad D. Barrows‡, and Raffi V. Aroian†‡ *Program in International Child Health, Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520; and ‡Section of Cell and Developmental Biology, University of California, San Diego, CA 92093 Communicated by Bruce Alberts, University of California, San Francisco, CA, August 14, 2006 (received for review June 20, 2006) Crystal (Cry) proteins produced by the soil bacterium Bacillus nearly 24% of all of the cotton grown in the world expressed a thuringiensis (Bt) are harmless to vertebrates, but they are highly Cry protein (18). The tremendous success of this natural product toxic to insects and nematodes. Their value in controlling insects is the result of multiple factors, including high efficacy, the that destroy crops and transmit human diseases is well established. absence of toxicity of Cry proteins toward mammals and other Although it has recently been demonstrated that a few individual vertebrates, and the ability to produce Cry proteins inexpensively Bt Cry proteins, such as Cry5B, are toxic to a wide range of and in large quantities. Recently, three Bt Cry proteins, Cry5B, free-living nematodes, the potential activity of purified Cry pro- Cry14A, and Cry21A, were identified that are toxic to both teins against parasitic nematodes remains largely unknown. We free-living nematodes (roundworms) and the free-living stage of report here studies aimed at characterizing in vitro and in vivo at least one parasitic nematode (15). These data raise the anthelminthic activities of purified recombinant Cry5B against the possibility that Cry proteins could provide a therapy for STN hookworm parasite Ancylostoma ceylanicum, a bloodfeeding gas- infections. trointestinal nematode for which humans are permissive hosts. By We report here that the purified recombinant Cry5B protein using in vitro larval development assays, Cry5B was found to be is highly active against the hookworm Ancylostoma ceylanicum, highly toxic to early stage hookworm larvae. Exposure of adult A. a parasitic nematode for which humans are permissive hosts ceylanicum to Cry5B was also associated with significant toxicity, (19–21). By using in vitro culture methods, we demonstrate that including a substantial reduction in egg excretion by adult female Cry5B targets multiple stages of hookworm development, in- worms. To demonstrate therapeutic efficacy in vivo, hamsters cluding the intestinal bloodfeeding stage. We demonstrate that infected with A. ceylanicum were treated with three daily oral oral administration of purified Cry5B to hamsters infected with doses of purified Cry5B, the benzimidazole anthelminthic meb- A. ceylanicum provides significant benefit in vivo, effecting a cure endazole, or buffer. Compared with control (buffer-treated) ani- of the hookworm infection comparable with that achieved with mals, infected hamsters that received Cry5B showed statistically mebendazole. Together, these data suggest that Bt Cry proteins significant improvements in growth and blood hemoglobin levels have tremendous potential for treatment of parasitic nematode as well as reduced worm burdens that were comparable to the infections of humans and other mammals. mebendazole-treated animals. These data demonstrate that Cry5B is highly active in vitro and in vivo against a globally significant Results nematode parasite and that Cry5B warrants further clinical devel- Adult Hookworms Express Receptors for Cry5B. To determine opment for human and veterinary use. whether the hookworm A. ceylanicum was susceptible to the nematicidal Bt Cry protein Cry5B, we investigated whether A. anthelminthic ͉ Cry5B ͉ nematode ceylanicum adults express a Cry5B receptor. As previously shown, the receptors for Cry5B in Caenorhabditis elegans are the oil-transmitted nematode (STN) infections represent a ma- carbohydrate moieties present on invertebrate-specific glycolip- Sjor cause of morbidity in developing countries, with an ids (22). Because glycolipids are well conserved among nema- estimated burden of human disease comparable with that of todes (23), we hypothesized that Ancylostoma hookworms would malaria or tuberculosis (1–3). In addition to human health, similarly express Cry5B receptors. We extracted glycolipids from animal nematode infections are of major veterinary significance, C. elegans and A. ceylanicum, resolved them by TLC, and resulting in millions of dollars of lost revenue for industries that performed an overlay͞binding experiment with biotinylated provide products and food from livestock, including cattle and Cry5B protein. As shown in Fig. 1, Cry5B binds multiple sheep (4–8). Although anti-nematode drugs (anthelminthics) glycolipid species in both C. elegans and A. ceylanicum. Binding exist, there are well founded concerns about the emergence of of Cry5B to C. elegans glycolipids was specifically inhibited in the resistance to these compounds. Hence, there exists a pressing presence of galactose but not glucose. Hookworm receptors need to develop new, safe, and inexpensive agents for the demonstrated similar specificity because the addition of 80 mM treatment of human and veterinary nematode infections of galactose to the binding experiment reduced (but did not global significance (8–12). Bacillus thuringiensis (Bt) crystal (Cry) proteins are the most widely used, biologically produced insecticides in the world (13). Author contributions: M.C., R.D.B., L.M.H., and R.V.A. designed research; R.D.B., L.M.H., and J.S.G. performed research; L.J.B. and B.D.B. contributed new reagents͞analytic tools; Bt is a soil bacterium that produces large crystalline inclusions M.C., R.D.B., L.M.H., and R.V.A. analyzed data; and M.C., R.D.B., L.M.H., and R.V.A. wrote during sporulation. These crystals contain one or several Cry the paper. proteins that are highly toxic to invertebrates but nontoxic The authors declare no conflict of interest. toward vertebrates (14, 15). For decades, Cry proteins have been Abbreviations: Bt, Bacillus thuringiensis; Cry, crystal; epg, eggs per gram; HCM, hookworm applied in large quantities to kill both insects that eat plants and culture medium; PI, postinfection; STN, soil-transmitted nematode. insects that vector viruses and helminth parasites (16). Trans- †To whom correspondence may be addressed. E-mail: [email protected] or genic corn and cotton expressing Bt Cry proteins for caterpillar [email protected]. protection have been planted for the past decade (17). In 2005, © 2006 by The National Academy of Sciences of the USA 15154–15159 ͉ PNAS ͉ October 10, 2006 ͉ vol. 103 ͉ no. 41 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0607002103 Downloaded by guest on October 4, 2021 Fig. 1. A. ceylanicum extracts contain Cry5B-binding glycolipids. Upper- phase glycolipids were extracted from mixed-stage C. elegans (Ce) and adult A. ceylanicum (Ac) and separated by TLC. The separated glycolipids were then subjected to a Cry5B overlay in the presence of 80 mM glucose (Glc) (left lanes) or 80 mM galactose (Gal) (right lanes). Cry5B bound to glycolipids from both nematodes in a galactose-dependent fashion. eliminate) binding of Cry5B to glycolipids from A. ceylanicum (Fig. 1). These data confirm that A. ceylanicum, like C. elegans, expresses Cry5B glycolipid receptors. Fig. 2. Effects of Cry5B on A. ceylanicum adults in vitro.(A) Six micrograms of purified Cry5B (lane 2) was subjected to SDS͞PAGE and Coomassie blue staining. (B) Exposure to Cry5B impairs motility of adult hookworms. Groups Effect of Cry5B Toxin on Adult Hookworms in Vitro. We evaluated the of 10 adult A. ceylanicum worms were cultured in increasing concentrations susceptibility of A. ceylanicum to Bt toxin by culturing adult of purified Cry5B toxin. Motility was monitored at the times indicated, and the worms in the presence of purified recombinant Cry5B (24) (Fig. data represent the mean values (ϮSE) of triplicate wells containing each 2A). The toxicity of Cry5B against adult worms as measured by concentration of toxin. Statistically significant (P Ͻ 0.001) differences in motility was noted at all concentrations tested (Fig. 2B). In motility were observed between control worms (buffer only) and worms contrast, the motility of adult hookworms maintained in stan- cultured in 50 or 200 ␮g͞ml Cry5B toxin throughout the observation period dard culture medium alone remained at 95% or greater through- (24–120 h). Statistically significant differences (P Ͻ 0.001) between control ␮ ͞ ␮ ͞ out the observation period. worms (0 g ml) and the 5 g ml toxin group were detected from 42–120 h Cry5B toxin also reduced egg release by female hookworms in culture. (C) Cry5B toxin reduces A. ceylanicum egg excretion. Adult female hookworms were maintained for 24 h in the presence of increasing concen- (Fig. 2C). Control worms cultured in the absence of toxin Ϯ trations of purified Cry5B toxin. Experimental groups consisted of four repli- released a mean of 2,150 475 eggs over 24 h. Worms cultured cate wells (three worms per well) at each concentration of toxin. Values in the lowest concentration of toxin (0.01 ␮g͞ml) excreted fewer represent the mean number of eggs (ϮSE) counted in each well. P values eggs (1,634 Ϯ 320), although this difference was not statistically represent statistical comparisons between each group and the control worms significant. In contrast, females exposed to 0.1 ␮g͞ml or 1 ␮g͞ml (no toxin). Cry5B demonstrated an Ϸ95% reduction in the number of eggs excreted (121 Ϯ 31 and 97 Ϯ 33, respectively) compared with ␮ ͞ Ϯ control worms, differences that were statistically significant (P Ͻ cultured in the presence of 10 g ml Cry5B, with 6 2% Ͻ 0.05). These concentrations of toxin did not impair the motility motility (P 0.01 compared with control) observed at 48 h. Our of adult females, and they are consistent with previous obser- data thus indicate that early stage larvae are more sensitive to the vations in free-living nematodes that progeny production is effects of Cry5B than adult hookworms (compare Figs.
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