ExcretorySecretory-Products of Echinococcus multilocularis Larvae Induce Apoptosis and Tolerogenic Properties in Dendritic Cells In Vitro 英文参考文献.docVIP

Excretory/Secretory-ProductsofEchinococcus multilocularisLarvaeInduceApoptosisandTolerogenic PropertiesinDendriticCellsInVitro JustinKomguepNono1,KatrienPletinckx2,ManfredB.Lutz2,KlausBrehm1* 1University of Wu¨rzburg, Institute of Hygiene and Microbiology, Wu¨rzburg, Germany, 2University of Wu¨rzburg, Institute of Virology and Immunobiology, Wu¨rzburg, Germany Abstract Background: Alveolar echinococcosis, caused by Echinococcus multilocularis larvae, is a chronic disease associated with considerable modulation of the host immune response. Dendritic cells (DC) are key effectors in shaping the immune response and among the first cells encountered by the parasite during an infection. Although it is assumed that E.multilocularis,byexcretory/secretory(E/S)-products,specificallyaffectsDCtodeviateimmuneresponses,littleinformation isavailableonthemolecularnatureofrespectiveE/S-productsandtheirmodeofaction. Methodology/Principal Findings: We established cultivation systems for exposing DC to live material from early (oncosphere),chronic(metacestode)andlate(protoscolex)infectiousstages.Whenco-incubatedwithEchinococcusprimary cells,representingtheinvadingoncosphere,ormetacestodevesicles,asignificantproportionofDCunderwentapoptosis andthesurvivingDCfailedtomature.Incontrast,DCexposedtoprotoscolecesupregulatedmaturationmarkersanddid notundergoapoptosis.Afterpre-incubationwithprimarycellsandmetacestodevesicles,DCshowedastronglyimpaired ability to be activated by the TLR ligand LPS, which was not observed in DC pre-treated with protoscolex E/S-products. Whilenoneofthelarvaeinducedthesecretionofpro-inflammatoryIL-12p70,theproductionofimmunosuppressiveIL-10 waselevatedinresponsetoprimarycellE/S-products.Finally,uponincubationwithDCandna?¨veT-cells,E/S-productsfrom metacestodevesiclesledtoasignificantexpansionofFoxp3+Tcellsinvitro. Conclusions:ThisisthefirstreportontheinductionofapoptosisinDCbycestodeE/S-products.Ourdataindicatethatthe early infective stage of E. multilocularis is