Vaccination with a defined Francisella tularensis subsp. novicida pathogenicity island mutant (DeltaiglB) induces protective immunity against homotypic and heterotypic challenge.
Francisella tularensis, an intracellular Gram-negative bacterium, is the causative agent of tularemia and a potential bioweapon. Currently, there is no licensed vaccine against this organism. We have characterized the efficacy of a defined F. tularensis subsp. novicida mutant (DeltaiglB) as a live attenuated vaccine against pneumonic tularemia. Replication of the iglB mutant (KKF235) in murine macrophages was significantly lower than the wild type novicida strain U112, and exhibited an LD(50) greater than 10(6)-fold (>10(7)CFU vs <10CFU) in an intranasal challenge model. Mice immunized with KKF235 intranasally or orally induced robust antigen-specific splenic IFN-gamma recall responses, as well as the production of systemic and mucosal antibodies. Intranasal vaccination with KKF235 protected mice from subsequent homotypic challenge with U112 as well as heterotypic challenge with F. tularensis subsp. holarctica (LVS). Moreover, protected animals also exhibited minimal pathological changes compared with mock-vaccinated and challenged animals. The protection conferred by KKF235 vaccination was shown to be highly dependent on endogenous IFN-gamma production. Most significantly, oral immunization with KKF235 protected mice from a highly lethal subsp. tularensis (SCHU S4) pulmonary challenge. Collectively, these results further suggest the feasibility of using defined pathogenicity island mutants as live vaccine candidates against pneumonic tularemia.
Cong
Yu
Y
South Texas Center for Emerging Infectious Diseases and Department of Biology, University of Texas at San Antonio, San Antonio, TX 78249, USA.
Yu
Jieh-Juen
JJ
Guentzel
M Neal
MN
Berton
Michael T
MT
Seshu
Janakiram
J
Klose
Karl E
KE
Arulanandam
Bernard P
BP
D000284:Administration, Oral; D000818:Animals; D000907:Antibodies, Bacterial / Q000032:analysis / Q000097:blood; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D015169:Colony Count, Microbial; D005260:Female; D005604:Francisella tularensis / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D017353:Gene Deletion; D005798:Genes, Bacterial; D044404:Genomic Islands; D007371:Interferon-gamma / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008264:Macrophages / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050296:Microbial Viability; D013154:Spleen / Q000276:immunology; D016019:Survival Analysis; D014406:Tularemia / Q000517:prevention & control*; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology
D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines; D014613:Vaccines, Attenuated; D007371:Interferon-gamma