Pleiotropic effects of the lpxM mutation in Yersinia pestis resulting in modification of the biosynthesis of major immunoreactive antigens

Feodorova, Valentina A.; Pan'kina, L. N.; Savostina, E. P.; Kuznetsov, O. S.; Konnov, Nikolai P.; Sayapina, L. V.; Dentovskaya, Svetlana V.; Shaikhutdinova, Rima Z.; Ageev, S. A.; Lindner, Buko; Kondakova, Anna N.; Bystrova, Olga V.; Kocharova, Nina A.; Senchenkova, Sof’ya N.; Holst, Otto; Pier, Gerald B.; Knirel, Yuriy A.; Anisimov, Andrey P.; Motin, Vladimir L.

doi:10.1016/j.vaccine.2009.02.020

Cited by 24 publications

(24 citation statements)

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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: 90%

“…The capsular antigen (F1) of Y. pestis has antiphagocytic properties and is also a major immunoreactive antigen (39,46). Therefore, we examined the production of F1 antigen in all strains by using a commercial dipstick kit as well as by IF staining.…”

Section: Resultsmentioning

confidence: 99%

“…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%

“…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%

“…This vaccine strain is preferably grown at 28°C due to the observation that Y. pestis cells are more viable and survive long-term storage better at this temperature (14,37). Consequently, these vaccines are not licensed in Western countries (5,39).…”

mentioning

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: 90%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

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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Assessment of Live Plague Vaccine Candidates

Feodorova

Sayapina

Motin

2016

Methods in Molecular Biology

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Since its creation in the early twentieth century, live plague vaccine EV has been successfully applied to millions of people without severe complications. This vaccine has been proven to elicit protection against both bubonic and pneumonic plague, and it is still in use in populations at risk mainly in the countries of the former Soviet Union. Despite extensive efforts in developing subunit vaccines, there is a reviving interest in creation of a precisely attenuated strain of Yersinia pestis superior to the EV that can serve as a live plague vaccine with improved characteristics. Here we summarize decades of experience of the Russian anti-plague research in developing a standard protocol for early-stage evaluation of safety and immunogenicity of live plague vaccines. This protocol allows step-by-step comparison of the novel test candidates with the EV vaccine by using subcutaneous immunization and bubonic plague infection models in two animal species, e.g., guinea pigs and mice.

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