Effect of deletion of the lpxM gene on virulence and vaccine potential of Yersinia pestis in mice

Anisimov, Andrey P.; Shaikhutdinova, Rima Z.; Pan'kina, L. N.; Feodorova, Valentina A.; Savostina, E. P.; Bystrova, Olga V.; Lindner, Buko; Мокриевич, А. Н.; Бахтеева, И. В.; Титарева, Г. М.; Dentovskaya, Svetlana V.; Kocharova, Nina A.; Senchenkova, Sof’ya N.; Holst, Otto; Devdariani, Z. L.; Popov, Yuriy A.; Pier, Gerald B.; Knirel, Yuriy A.

doi:10.1099/jmm.0.46880-0

Cited by 36 publications

(34 citation statements)

References 62 publications

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“…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%

“…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%

“…Unlike the other two enteropathogenic Yersinia species (Y. pseudotuberculosis and Y. enterocolitica), Y. pestis synthesizes a rough LPS which lacks the O antigen (14,15). Interestingly, the change from tetra-acylated lipid A at 37°C to hexa-acylated lipid A at 21 to 27°C is the characteristic trait for all yersiniae (9,(16)(17)(18)(19)(20), and it is the absence of hexa-acylated lipid A in yersiniae at 37°C that prevents activation of Toll-like receptor 4 (TLR-4) (9,16,18,20).…”

mentioning

confidence: 99%

“…Although Y. pestis synthesizes less potent tetra-acylated LPS at 37°C, the current live plague vaccines, such as the EV76 strain, used in the countries of the former Soviet Union, is usually grown at 28°C. At this temperature, Y. pestis synthesizes the highly potent hexa-acylated LPS (14,37), and it is used for human immunization as a single dose of 5.8 ϫ 10 6 CFU (38). 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).…”

mentioning

confidence: 99%

“…At this temperature, Y. pestis synthesizes the highly potent hexa-acylated LPS (14,37), and it is used for human immunization as a single dose of 5.8 ϫ 10 6 CFU (38). 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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