title: Neutralization of Yersinia pestis-mediated macrophage cytotoxicity by anti-LcrV antibodies and its correlation with protective immunity in a mouse model of bubonic plague.
abstract: Plague is a life-threatening disease caused by Yersinia pestis, for which effective-licensed vaccines and reliable predictors of in vivo immunity are lacking. V antigen (LcrV) is a major Y. pestis virulence factor that mediates translocation of the cytotoxic Yersinia protein effectors (Yops). It is a well-established protective antigen and a part of currently tested plague subunit vaccines. We have developed a highly sensitive in vitro macrophage cytotoxicity neutralization assay which is mediated by anti-LcrV antibodies; and studied the potential use of these neutralizing antibodies as an in vitro correlate of plague immunity in mice. The assay is based on a Y. pestis strain with enhanced cytotoxicity to macrophages in which endogenous yopJ was replaced by the more effectively translocated yopP of Y. enterocolitica O:8. Mice passively immunized with rabbit anti-LcrV IgG or actively immunized with recombinant LcrV were protected against lethal doses of a virulent Y. pestis strain, in a mouse model of bubonic plague. This protection significantly correlated with the in vitro neutralizing activity of the antisera but not with their corresponding ELISA titers. In actively immunized mice, a cutoff value for serum neutralizing activity, above which survival was assured with high degree of confidence, could be established for different vaccination regimes. The impact of overall findings on the potential use of serum neutralizing activity as a correlate of protective immunity is discussed.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Israel Institute for Biological Research, Ness-Ziona, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Zauberman
authors.forename: Sara
authors.initials: S
authors.lastname: Cohen
authors.forename: Yinon
authors.initials: Y
authors.lastname: Levy
authors.forename: Gideon
authors.initials: G
authors.lastname: Halperin
authors.forename: Shirley
authors.initials: S
authors.lastname: Lazar
authors.forename: Baruch
authors.initials: B
authors.lastname: Velan
authors.forename: Avigdor
authors.initials: A
authors.lastname: Shafferman
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Flashner
authors.forename: Emanuelle
authors.initials: E
authors.lastname: Mamroud
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000494:pharmacology* / Q000633:toxicity; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000942:Antigens, Bacterial / Q000276:immunology*; D002460:Cell Line; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007115:Immunization Schedule; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics / Q000633:toxicity; D007928:Lethal Dose 50; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009500:Neutralization Tests; D010930:Plague / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*; D052899:Pore Forming Cytotoxic Proteins / Q000276:immunology*; D011817:Rabbits; D014614:Vaccines, Synthetic / Q000096:biosynthesis / Q000235:genetics; D015010:Yersinia pestis / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D007074:Immunoglobulin G; C043908:LcrV protein, Yersinia; D052899:Pore Forming Cytotoxic Proteins; D014614:Vaccines, Synthetic