title: An improved vaccine for prevention of respiratory tularemia caused by Francisella tularensis SchuS4 strain.
abstract: Vaccination of mice with Francisella tularensis live vaccine strain (LVS) mutants described so far have failed to induce protection in C57BL/6 mice against challenge with the virulent strain F. tularensis SchuS4. We have previously reported that a mutant of F. tularensis LVS deficient in iron superoxide dismutase (sodB(Ft)) is hypersensitive to oxidative stress and attenuated for virulence in mice. Herein, we evaluated the efficacy of this mutant as a vaccine candidate against respiratory tularemia caused by F. tularensis SchuS4. C57BL/6 mice were vaccinated intranasally (i.n.) with the sodB(Ft) mutant and challenged i.n. with lethal doses of F. tularensis SchuS4. The level of protection against SchuS4 challenge was higher in sodB(Ft) vaccinated group as compared to the LVS vaccinated mice. sodB(Ft) vaccinated mice following SchuS4 challenge exhibited significantly reduced bacterial burden in lungs, liver and spleen, regulated production of pro-inflammatory cytokines and less severe histopathological lesions compared to the LVS vaccinated mice. The sodB(Ft) vaccination induced a potent humoral immune response and protection against SchuS4 required both CD4 and CD8 T cells in the vaccinated mice. sodB(Ft) mutants revealed upregulated levels of chaperonine proteins DnaK, GroEL and Bfr that have been shown to be important for generation of a potent immune response against Francisella infection. Collectively, this study describes an improved live vaccine candidate against respiratory tularemia that has an attenuated virulence and enhanced protective efficacy than the LVS.
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA. bakshis@mail.amc.edu
authors.forename: Chandra Shekhar
authors.initials: CS
authors.lastname: Bakshi
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Malik
authors.forename: Manish
authors.initials: M
authors.lastname: Mahawar
authors.forename: Girish S
authors.initials: GS
authors.lastname: Kirimanjeswara
authors.forename: Karsten R O
authors.initials: KR
authors.lastname: Hazlett
authors.forename: Lance E
authors.initials: LE
authors.lastname: Palmer
authors.forename: Martha B
authors.initials: MB
authors.lastname: Furie
authors.forename: Rajendra
authors.initials: R
authors.lastname: Singh
authors.forename: J Andres
authors.initials: JA
authors.lastname: Melendez
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Sellati
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Metzger
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001426:Bacterial Proteins / Q000235:genetics; D001428:Bacterial Vaccines / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D005604:Francisella tularensis / Q000235:genetics / Q000276:immunology*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012141:Respiratory Tract Infections / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000235:genetics; D016019:Survival Analysis; D014406:Tularemia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015854:Up-Regulation; D015164:Vaccines, Inactivated / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D001428:Bacterial Vaccines; D016207:Cytokines; D006360:Heat-Shock Proteins; D015164:Vaccines, Inactivated; C087504:SodB protein, Bacteria; D013482:Superoxide Dismutase