Bacillus thuringiensis-derived Cry5B Has Potent Anthelmintic Activity against Ascaris suum.docVIP

Bacillus thuringiensis-derived Cry5B Has Potent Anthelmintic Activity against Ascaris suum.doc

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Bacillus thuringiensis-derived Cry5B Has Potent Anthelmintic Activity against Ascaris suum

Bacillusthuringiensis-derivedCry5BHasPotent AnthelminticActivityagainstAscarissuum JosephF.Urban,Jr.1.,YanHu2.,MelanieM.Miller2,UlrikeScheib2,YingY.Yiu2,RaffiV.Aroian2* 1USDA,AgriculturalResearchService, BeltsvilleHuman Nutrition ResearchCenter, Diet,Genomics,andImmunologyLaboratory, Beltsville, Maryland,United States of America,2SectionofCellandDevelopmentalBiology,DivisionofBiologicalSciences,UniversityofCalifornia,SanDiego,LaJolla,California,UnitedStatesofAmerica Abstract Ascaris suum and Ascaris lumbricoides are two closely related geo-helminth parasites that ubiquitously infect pigs and humans, respectively. Ascaris suum infection in pigs is considered agood model for A. lumbricoides infection in humans becauseofasimilarbiologyandtissuemigrationtotheintestines.Ascarislumbricoidesinfectionsinchildrenareassociated withmalnutrition,growthandcognitivestunting,immunedefects,and,inextremecases,life-threateningblockageofthe digestivetractandaberrantmigrationintothebileductandperitoneum.SimilareffectscanbeseenwithA.suuminfections inpigsrelatedtopoorfeedefficiencyandperformance.NewstrategiestocontrolAscarisinfectionsareneededlargelydue toreducedtreatmentefficaciesofcurrentanthelminticsinthefield,thethreatofresistancedevelopment,andthegeneral lackofnewdrugdevelopmentforintestinalsoil-transmittedhelminthsforhumansandanimals.Herewedemonstratefor thefirsttimethatA.suumexpressesthereceptorsforBacillusthuringiensiscrystalproteinandnovelanthelminticCry5B, whichhasbeenpreviouslyshowntointoxicatehookwormsandwhichbelongstoaclassofproteinsconsiderednon-toxic tovertebrates.Cry5BisabletointoxicateA.suumlarvaeandadultsandtriggerstheactivationofthep38mitogen-activated proteinkinasepathwaysimilartothatobservedwithothernematodes.Mostimportantly,twomoderatedosesof20mg/kg bodyweight(143nM/kg)ofCry5BresultedinanearcompletecureofintestinalA.suuminfectionsinpigs.Takentogether, theseresultsdemonstratetheexcellentpotentialofCry5BtotreatAscarisinfectionsinpigsandinhumansandforCry5Bto work

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