title: Intramuscular Immunization of Mice with a Live-Attenuated Triple Mutant of Yersinia pestis CO92 Induces Robust Humoral and Cell-Mediated Immunity To Completely Protect Animals against Pneumonic Plague.
abstract: Earlier, we showed that the Δlpp ΔmsbB Δail triple mutant of Yersinia pestis CO92 with deleted genes encoding Braun lipoprotein (Lpp), an acyltransferase (MsbB), and the attachment invasion locus (Ail), respectively, was avirulent in a mouse model of pneumonic plague. In this study, we further evaluated the immunogenic potential of the Δlpp ΔmsbB Δail triple mutant and its derivative by different routes of vaccination. Mice were immunized via the subcutaneous (s.c.) or the intramuscular (i.m.) route with two doses (2 × 10(6) CFU/dose) of the above-mentioned triple mutant with 100% survivability of the animals. Upon subsequent pneumonic challenge with 70 to 92 50% lethal doses (LD(50)) of wild-type (WT) strain CO92, all of the mice survived when immunization occurred by the i.m. route. Since Ail has virulence and immunogenic potential, a mutated version of Ail devoid of its virulence properties was created, and the genetically modified ail replaced the native ail gene on the chromosome of the Δlpp ΔmsbB double mutant, creating a Δlpp ΔmsbB::ailL2 vaccine strain. This newly generated mutant was attenuated similarly to the Δlpp ΔmsbB Δail triple mutant when administered by the i.m. route and provided 100% protection to animals against subsequent pneumonic challenge. Not only were the two above-mentioned mutants cleared rapidly from the initial i.m. site of injection in animals with no histopathological lesions, the immunized mice did not exhibit any disease symptoms during immunization or after subsequent exposure to WT CO92. These two mutants triggered balanced Th1- and Th2-based antibody responses and cell-mediated immunity. A substantial increase in interleukin-17 (IL-17) from the T cells of vaccinated mice, a cytokine of the Th17 cells, further augmented their vaccine potential. Thus, the Δlpp ΔmsbB Δail and Δlpp ΔmsbB::ailL2 mutants represent excellent vaccine candidates for plague, with the latter mutant still retaining Ail immunogenicity but with a much diminished virulence potential.
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Tiner
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA jisha@utmb.edu achopra@utmb.edu.
authors.forename: Jian
authors.initials: J
authors.lastname: Sha
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Duraisamy
authors.initials: D
authors.lastname: Ponnusamy
authors.affiliation: Department of Veterinary Sciences, University of Texas MD Anderson Cancer Center, Bastrop, Texas, USA.
authors.forename: Wallace B
authors.initials: WB
authors.lastname: Baze
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Fitts
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Vsevolod L
authors.initials: VL
authors.lastname: Popov
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Christina J
authors.initials: CJ
authors.lastname: van Lier
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Tatiana E
authors.initials: TE
authors.lastname: Erova
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA jisha@utmb.edu achopra@utmb.edu.
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Chopra
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D017353:Gene Deletion; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D007114:Immunization; D007273:Injections, Intramuscular; D008074:Lipoproteins / Q000276:immunology; D051379:Mice; D009154:Mutation; D010930:Plague / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D010931:Plague Vaccine / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology; D015010:Yersinia pestis / Q000235:genetics* / Q000276:immunology*
chemical_list: D001426:Bacterial Proteins; D008074:Lipoproteins; D010931:Plague Vaccine; D014613:Vaccines, Attenuated