Correlates of protection following vaccination of mice with gene deletion mutants of Francisella tularensis subspecies tularensis strain, SCHU S4 that elicit varying degrees of immunity to systemic and respiratory challenge with wild-type bacteria

Rydén, Patrik; Twine, Susan M.; Shen, Hua; Harris, Greg; Chen, Wangxue; Sjöstedt, Anders; Conlan, Wayne

doi:10.1016/j.molimm.2012.10.043

Cited by 28 publications

(50 citation statements)

References 34 publications

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“…F. tularensis-specific antibody production was enhanced after vaccination with catanionic vesicles containing LVS particles (Fig. 2), while previous studies were unable to correlate F. tularensis-specific antibody production with protection (60,61). T helper cells must be activated in our system, as most of the F. tularensis-specific antibodies produced in response to LVS-V-immunization are of the IgG isotype (Fig.…”

Section: Discussionmentioning

confidence: 83%

“…Moreover, live attenuated F. tularensis strains, such as the ⌬clpB strain, elicit early inflammatory responses and induce immunity to F. tularensis LVS (35)(36)(37). Immunization with attenuated Schu S4 mutants capable of protecting mice against subsequent virulent Schu S4 challenge was shown to correlate with higher blood serum levels of TNF-␣, IFN-␥, and MCP-1 within the first week postinfection than immunization with nonprotective mutants (60). The administration of F. tularensis components integrated into a catanionic vesicle also introduced F. tularensis antigens in an inflammatory context, as evidenced by an increase in inflammatory cytokines as early as 4 h after vaccination (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Novel Catanionic Surfactant Vesicle Vaccines Protect against Francisella tularensis LVS and Confer Significant Partial Protection against F. tularensis Schu S4 Strain

Richard¹,

Mann²,

Stocker³

et al. 2013

Clin. Vaccine Immunol.

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g Francisella tularensis is a Gram-negative immune-evasive coccobacillus that causes tularemia in humans and animals. A safe and efficacious vaccine that is protective against multiple F. tularensis strains has yet to be developed. In this study, we tested a novel vaccine approach using artificial pathogens, synthetic nanoparticles made from catanionic surfactant vesicles that are functionalized by the incorporation of either

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Novel Catanionic Surfactant Vesicle Vaccines Protect against Francisella tularensis LVS and Confer Significant Partial Protection against F. tularensis Schu S4 Strain

Richard¹,

Mann²,

Stocker³

et al. 2013

Clin. Vaccine Immunol.

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“…Recent efforts to develop a tularemia vaccine have focused on live attenuated vaccines using site-specific deletion of virulence genes (3,(19)(20)(21)(22)(23)(24)(25)(26)(27). Studies have identified a number of mutations that attenuate F. tularensis to various degrees.…”

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confidence: 99%

Live Attenuated Mutants of Francisella tularensis Protect Rabbits against Aerosol Challenge with a Virulent Type A Strain

et al. 2014

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c Francisella tularensis, a Gram-negative bacterium, is the causative agent of tularemia. No licensed vaccine is currently available for protection against tularemia, although an attenuated strain, dubbed the live vaccine strain (LVS), is given to at-risk laboratory personnel as an investigational new drug (IND). In an effort to develop a vaccine that offers better protection, recombinant attenuated derivatives of a virulent type A strain, SCHU S4, were evaluated in New Zealand White (NZW) rabbits. Rabbits vaccinated via scarification with the three attenuated derivatives (SCHU S4 ⌬guaBA, ⌬aroD, and ⌬fipB strains) or with LVS developed a mild fever, but no weight loss was detected. Twenty-one days after vaccination, all vaccinated rabbits were seropositive for IgG to F. tularensis lipopolysaccharide (LPS). Thirty days after vaccination, all rabbits were challenged with aerosolized SCHU S4 at doses ranging from 50 to 500 50% lethal doses (LD 50 ). All rabbits developed fevers and weight loss after challenge, but the severity was greater for mock-vaccinated rabbits. The ⌬guaBA and ⌬aroD SCHU S4 derivatives provided partial protection against death (27 to 36%) and a prolonged time to death compared to results for the mock-vaccinated group. In contrast, LVS and the ⌬fipB strain both prolonged the time to death, but there were no survivors from the challenge. This is the first demonstration of vaccine efficacy against aerosol challenge with virulent type A F. tularensis in a species other than a rodent since the original work with LVS in the 1960s. The ⌬guaBA and ⌬aroD SCHU S4 derivatives warrant further evaluation and consideration as potential vaccines for tularemia and for identification of immunological correlates of protection.

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“…tularensis strains. Several such vaccine candidates have been characterized more recently (11)(12)(13)(14)(15)(16)(17)(18).…”

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confidence: 99%

Identification of Mechanisms for Attenuation of the FSC043 Mutant of Francisella tularensis SCHU S4

et al. 2014

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bPreviously, we identified a spontaneous, essentially avirulent mutant, FSC043, of the highly virulent strain SCHU S4 of Francisella tularensis subsp. tularensis. We have now characterized the phenotype of the mutant and the mechanisms of its attenuation in more detail. Genetic and proteomic analyses revealed that the pdpE gene and most of the pdpC gene were very markedly downregulated and, as previously demonstrated, that the strain expressed partially deleted and fused fupA and fupB genes. FSC043 showed minimal intracellular replication and induced no cell cytotoxicity. The mutant showed delayed phagosomal escape; at 18 h, colocalization with LAMP-1 was 80%, indicating phagosomal localization, whereas the corresponding percentages for SCHU S4 and the ⌬fupA mutant were <10%. However, a small subset of the FSC043-infected cells contained up to 100 bacteria with LAMP-1 colocalization of around 30%. The unusual intracellular phenotype was similar to that of the ⌬pdpC and ⌬pdpC ⌬pdpE mutants. Complementation of FSC043 with the intact fupA and fupB genes did not affect the phenotype, whereas complementation with the pdpC and pdpE genes restored intracellular replication and led to marked virulence. Even higher virulence was observed after complementation with both double-gene constructs. After immunization with the FSC043 strain, moderate protection against respiratory challenge with the SCHU S4 strain was observed. In summary, FSC043 showed a highly unusual intracellular phenotype, and based on our findings, we hypothesize that the mutation in the pdpC gene makes an essential contribution to the phenotype.

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Correlates of protection following vaccination of mice with gene deletion mutants of Francisella tularensis subspecies tularensis strain, SCHU S4 that elicit varying degrees of immunity to systemic and respiratory challenge with wild-type bacteria

Cited by 28 publications

References 34 publications

Novel Catanionic Surfactant Vesicle Vaccines Protect against Francisella tularensis LVS and Confer Significant Partial Protection against F. tularensis Schu S4 Strain

Novel Catanionic Surfactant Vesicle Vaccines Protect against Francisella tularensis LVS and Confer Significant Partial Protection against F. tularensis Schu S4 Strain

Live Attenuated Mutants of Francisella tularensis Protect Rabbits against Aerosol Challenge with a Virulent Type A Strain

Identification of Mechanisms for Attenuation of the FSC043 Mutant of Francisella tularensis SCHU S4

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