Mechanistic and Single-Dose In Vivo Therapeutic Studies of Cry5B Anthelmintic Action against Hookworms 英文参考文献.docVIP

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Mechanistic and Single-Dose In Vivo Therapeutic Studies of Cry5B Anthelmintic Action against Hookworms 英文参考文献.doc

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Mechanistic and Single-Dose In Vivo Therapeutic Studies of Cry5B Anthelmintic Action against Hookworms 英文参考文献

MechanisticandSingle-DoseInVivoTherapeuticStudies ofCry5BAnthelminticActionagainstHookworms YanHu1.,BinZhan2*.,BrianKeegan2,YingY.Yiu1,MelanieM.Miller1,KathrynJones2,RaffiV.Aroian1* 1SectionofCellandDevelopmentalBiology,UniversityofCaliforniaSanDiego,LaJolla,California,UnitedStatesofAmerica,2SectionofTropicalMedicine,Department ofPediatrics,BaylorCollegeofMedicine,Houston,Texas,UnitedStatesofAmerica Abstract Background:Hookworminfectionsareoneofthemostimportantparasiticinfectionsofhumansworldwide,consideredby some second only to malaria in associated disease burden. Single-dose mass drug administration for soil-transmitted helminths,includinghookworms,reliesprimarilyonalbendazole,whichhasvariableefficacy.Newandbetterhookworm therapiesareurgentlyneeded.BacillusthuringiensiscrystalproteinCry5Bhaspotentialasanovelanthelminticandhasbeen extensivelystudiedintheroundwormCaenorhabditiselegans.Here,weaskwhethersingle-doseCry5Bcanprovidetherapy againstahookworminfectionandwhetherC.elegansmechanism-of-actionstudiesarerelevanttohookworms. Methodology/Principal Findings: To test whether the C. elegans invertebrate-specific glycolipid receptor for Cry5B is relevantinhookworms,wefedAncylostomaceylanicumhookwormadultsCry5Bwithandwithoutgalactose,aninhibitorof Cry5B-C.elegansglycolipidinteractions.AswithC.elegans,galactoseinhibitsCry5BtoxicityinA.ceylanicum .Furthermore, p38 mitogen-activated protein kinase (MAPK), which controls one of the most important Cry5B signal transduction responsesinC.elegans,isfunctionallyoperationalinhookworms.A.ceylanicumhookwormstreatedwithCry5Bup-regulate p38MAPKandknockdownofp38MAPKactivityinhookwormsresultsinhypersensitivityofA.ceylanicumadultstoCry5B 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 activityisincreasedabout3-fold,eliminating.97%oftheparasiteswithasingle3m