title: Attenuated Francisella novicida transposon mutants protect mice against wild-type challenge.
abstract: Francisella tularensis is the bacterial pathogen that causes tularemia in humans and a number of animals. To date, there is no approved vaccine for this widespread and life-threatening disease. The goal of this study was to identify F. tularensis mutants that can be used in the development of a live attenuated vaccine. We screened F. novicida transposon mutants to identify mutants that exhibited reduced growth in mouse macrophages, as these cells are the preferred host cells of Francisella and an essential component of the innate immune system. This approach yielded 16 F. novicida mutants that were 100-fold more attenuated for virulence in a mouse model than the wild-type parental strain. These mutants were then tested to determine their abilities to protect mice against challenge with high doses of wild-type bacteria. Five of the 16 attenuated mutants (with mutations corresponding to dsbB, FTT0742, pdpB, fumA, and carB in the F. tularensis SCHU S4 strain) provided mice with protection against challenge with high doses (>8 x 10(5) CFU) of wild-type F. novicida. We believe that these findings will be of use in the design of a vaccine against tularemia.
authors.affiliation: 6543 Basic Sciences Addition/CROET Building, Department of Molecular Microbiology and Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA. tempelr@ohsu.edu
authors.forename: Rebecca
authors.initials: R
authors.lastname: Tempel
authors.forename: Xin-He
authors.initials: XH
authors.lastname: Lai
authors.forename: Lidia
authors.initials: L
authors.lastname: Crosa
authors.forename: Briana
authors.initials: B
authors.lastname: Kozlowicz
authors.forename: Fred
authors.initials: F
authors.lastname: Heffron
mesh_terms: D000818:Animals; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D002460:Cell Line; D004251:DNA Transposable Elements; D005260:Female; D005604:Francisella tularensis / Q000235:genetics* / Q000276:immunology*; D005798:Genes, Bacterial; D007928:Lethal Dose 50; D008099:Liver / Q000382:microbiology; D008168:Lung / Q000382:microbiology; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D013154:Spleen / Q000382:microbiology; D014406:Tularemia / Q000517:prevention & control*; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D001428:Bacterial Vaccines; D004251:DNA Transposable Elements; D014613:Vaccines, Attenuated