A Yersinia pestis lpxM-mutant live vaccine induces enhanced immunity against bubonic plague in mice and guinea pigs

Feodorova, Valentina A.; Pan'kina, L. N.; Savostina, E. P.; Sayapina, L. V.; Motin, Vladimir L.; Dentovskaya, Svetlana V.; Shaikhutdinova, Rima Z.; Ivanov, Sergey A.; Lindner, Buko; Kondakova, Anna N.; Bystrova, Olga V.; Kocharova, Nina A.; Сенченкова, С. Н.; Holst, Otto; Pier, Gerald B.; Knirel, Yuriy A.; Anisimov, Andrey P.

doi:10.1016/j.vaccine.2007.08.055

Cited by 40 publications

(46 citation statements)

References 25 publications

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“…Significant differences are indicated by lines, and P values shown are based on one-way ANOVA with the Bonferroni correction. The attenuation of virulence noted with our msbB mutants in both rodent models was thought to be due mainly to the production of the less toxic penta-acylated lipid A moiety of LPS, which is considered a common mechanism of reduced virulence for several other pathogenic bacteria (11,14,16,39,54,56,57). However, indistinguishable levels of cytokines/chemokines produced in the host during infection with both the WT bacteria and our msbB mutants at early stages of infection (i.e., 24 and 48 h p.i.)…”

Section: Discussionmentioning

confidence: 91%

“…Since the first report on the ⌬msbB mutant of E. coli (13), this gene has been deleted from several pathogenic bacteria, including S. enterica serovar Typhimurium, Neisseria meningitidis, Shigella flexneri, and Y. pestis (9,14,39,47,54,(56)(57)(58). Compared to the most toxic, hexa-acylated lipid A synthesized in WT bacteria, deletion of the msbB gene generally resulted in the production of a less toxic, penta-acylated lipid A in the mutant strains.…”

Section: Discussionmentioning

confidence: 99%

“…Compared to the most toxic, hexa-acylated lipid A synthesized in WT bacteria, deletion of the msbB gene generally resulted in the production of a less toxic, penta-acylated lipid A in the mutant strains. Almost all ⌬msbB mutants have been shown to be attenuated in both in vitro and in vivo models of infection (14,47,54,56,57).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, an ⌬lpxM (msbB) mutant generated in the Y. pestis strain EV line NIIEG was reported to have significantly reduced virulence and better immunogenicity in mouse and guinea pig models of bubonic plague (14,39,57). Further study of the Y. pestis EV ⌬lpxM mutant revealed pleiotropic effects of lpxM resulting in altered synthesis of major immunoreactive antigens, such as F1 antigen, low-calcium-response V antigen (LcrV), Pla (plasminogen-activating protease), Ymt (murine toxin), and surface-specific polysaccharides (SSP) (39).…”

Section: Discussionmentioning

confidence: 99%

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Deletion of the Braun Lipoprotein-Encoding Gene and Altering the Function of Lipopolysaccharide Attenuate the Plague Bacterium

et al. 2013

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e Braun (murein) lipoprotein (Lpp) and lipopolysaccharide (LPS) are major components of the outer membranes of Enterobacteriaceae family members that are capable of triggering inflammatory immune responses by activating Toll-like receptors 2 and 4, respectively. Expanding on earlier studies that demonstrated a role played by Lpp in Yersinia pestis virulence in mouse models of bubonic and pneumonic plague, we characterized an msbB in-frame deletion mutant incapable of producing an acyltransferase that is responsible for the addition of lauric acid to the lipid A moiety of LPS, as well as a ⌬lpp ⌬msbB double mutant of the highly virulent Y. pestis CO92 strain. Although the ⌬msbB single mutant was minimally attenuated, the ⌬lpp single mutant and the ⌬lpp ⌬msbB double mutant were significantly more attenuated than the isogenic wild-type (WT) bacterium in bubonic and pneumonic animal models (mouse and rat) of plague. These data correlated with greatly reduced survivability of the aforementioned mutants in murine macrophages. Furthermore, the ⌬lpp ⌬msbB double mutant was grossly compromised in its ability to disseminate to distal organs in mice and in evoking cytokines/chemokines in infected animal tissues. Importantly, mice that survived challenge with the ⌬lpp ⌬msbB double mutant, but not the ⌬lpp or ⌬msbB single mutant, in a pneumonic plague model were significantly protected against a subsequent lethal WT CO92 rechallenge. These data were substantiated by the fact that the ⌬lpp ⌬msbB double mutant maintained an immunogenicity comparable to that of the WT strain and induced long-lasting T-cell responses against heat-killed WT CO92 antigens. Taken together, the data indicate that deletion of the msbB gene augmented the attenuation of the ⌬lpp mutant by crippling the spread of the double mutant to the peripheral organs of animals and by inducing cytokine/chemokine responses. Thus, the ⌬lpp ⌬msbB double mutant could provide a new live-attenuated background vaccine candidate strain, and this should be explored in the future.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Deletion of the Braun Lipoprotein-Encoding Gene and Altering the Function of Lipopolysaccharide Attenuate the Plague Bacterium

et al. 2013

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“…28 Earlier work reported that guinea pigs immunized with live-attenuated vaccine strains, eg, Y. pestis M23 (F1 Ϫ ) 30 and EV (⌬pgm), 31 develop protection against s.c. challenge with fully virulent plague isolates. 28,32 When used for the testing of whole-cell-killed vaccines, the guinea pig model offered the same level of bubonic plague protection as did the mouse model. 33 Two subunit vaccines, F1V fusion and rLcrV ϩ rF1, were tested in guinea pigs and generated protection against s.c. challenge with fully virulent Y. pestis.…”

mentioning

confidence: 99%

Plague in Guinea Pigs and Its Prevention by Subunit Vaccines

Quenee

Ciletti

Berube

et al. 2011

The American Journal of Pathology

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Human pneumonic plague is a devastating and transmissible disease for which a Food and Drug Administration-approved vaccine is not available. Suitable animal models may be adopted as a surrogate for human plague to fulfill regulatory requirements for vaccine efficacy testing. To develop an alternative to pneumonic plague in nonhuman primates, we explored guinea pigs as a model system. On intranasal instillation of a fully virulent strain, Yersinia pestis CO92, guinea pigs developed lethal lung infections with hemorrhagic necrosis, massive bacterial replication in the respiratory system, and blood-borne dissemination to other organ systems. Expression of the Y. pestis F1 capsule was not required for the development of pulmonary infection; however, the capsule seemed to be important for the establishment of bubonic plague. The mean lethal dose (MLD) for pneumonic plague in guinea pigs was estimated to be 1000 colony-forming units. Immunization of guinea pigs with the recombinant forms of LcrV, a protein that resides at the tip of Yersinia type III secretion needles, or F1 capsule generated robust humoral immune responses. Whereas LcrV immunization resulted in partial protection against pneumonic plague challenge with 250 MLD Y. pestis CO92, immunization with recombinant F1 did not. rV10, a vaccine variant lacking LcrV residues 271-300, elicited protection against pneumonic plague, which seemed to be based on conformational antibodies directed against LcrV.

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