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Publication : Perforin- and granzyme-mediated cytotoxic effector functions are essential for protection against Francisella tularensis following vaccination by the defined F. tularensis subsp. novicida ΔfopC vaccine strain.

First Author  Sanapala S Year  2012
Journal  Infect Immun Volume  80
Issue  6 Pages  2177-85
PubMed ID  22493083 Mgi Jnum  J:186522
Mgi Id  MGI:5432467 Doi  10.1128/IAI.00036-12
Citation  Sanapala S, et al. (2012) Perforin- and granzyme-mediated cytotoxic effector functions are essential for protection against Francisella tularensis following vaccination by the defined F. tularensis subsp. novicida DeltafopC vaccine strain. Infect Immun 80(6):2177-85
abstractText  A licensed vaccine against Francisella tularensis is currently not available. Two Francisella tularensis subsp. novicida (herein referred to by its earlier name, Francisella novicida) attenuated strains, the DeltaiglB and DeltafopC strains, have previously been evaluated as potential vaccine candidates against pneumonic tularemia in experimental animals. F. novicida DeltaiglB, a Francisella pathogenicity island (FPI) mutant, is deficient in phagosomal escape and intracellular growth, whereas F. novicida DeltafopC, lacking the outer membrane lipoprotein FopC, which is required for evasion of gamma interferon (IFN-gamma)-mediated signaling, is able to escape and replicate in the cytosol. To dissect the difference in protective immune mechanisms conferred by these two vaccine strains, we examined the efficacy of the F. novicida DeltaiglB and DeltafopC mutants against pulmonary live-vaccine-strain (LVS) challenge and found that both strains provided comparable protection in wild-type, major histocompatibility complex class I (MHC I) knockout, and MHC II knockout mice. However, F. novicida DeltafopC-vaccinated but not F. novicida DeltaiglB-vaccinated perforin-deficient mice were more susceptible and exhibited greater bacterial burdens than similarly vaccinated wild-type mice. Moreover, perforin produced by natural killer (NK) cells and release of granzyme contributed to inhibition of LVS replication within macrophages. This NK cell-mediated LVS inhibition was enhanced with anti-F. novicida DeltafopC immune serum, suggesting antibody-dependent cell-mediated cytotoxicity (ADCC) in F. novicida DeltafopC-mediated protection. Overall, this study provides additional immunological insight into the basis for protection conferred by live attenuated F. novicida strains with different phenotypes and supports further investigation of this organism as a vaccine platform for tularemia.
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