Virulence Reduction in Yersinia pestis by Combining Delayed Attenuation with Plasmid Curing

Dentovskaya, Svetlana V.; Shaikhutdinova, Rima Z.; Platonov, Mikhail E.; Lipatnikova, Nadezhda A.; Mazurina, Elizaveta M.; Gapel’chenkova, Tat’yana V.; Kopylov, Pavel Kh.; Ivanov, Sergei A.; Trunyakova, Alexandra S.; Vagaiskaya, Anastasia S.; Anisimov, Andrey P.

doi:10.3390/biom16010040

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Virulence Reduction in Yersinia pestis by Combining Delayed Attenuation with Plasmid Curing

by

Svetlana V. Dentovskaya

,

Rima Z. Shaikhutdinova

,

Mikhail E. Platonov

,

Nadezhda A. Lipatnikova

,

Elizaveta M. Mazurina

,

Tat’yana V. Gapel’chenkova

,

Pavel Kh. Kopylov

,

Sergei A. Ivanov

,

Alexandra S. Trunyakova

,

Anastasia S. Vagaiskaya

and

Andrey P. Anisimov

^*

Laboratory for Plague Microbiology, Especially Dangerous Infections Department, State Research Center for Applied Microbiology and Biotechnology, 142279 Obolensk, Russia

^*

Author to whom correspondence should be addressed.

Biomolecules 2026, 16(1), 40; https://doi.org/10.3390/biom16010040 (registering DOI)

Submission received: 20 November 2025 / Revised: 18 December 2025 / Accepted: 23 December 2025 / Published: 25 December 2025

(This article belongs to the Section Molecular Biology)

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Abstract

Yersinia pestis caused the three plague pandemics that claimed more than two hundred million human lives. There is still no vaccine that meets all WHO requirements, and many researchers continue to develop plague vaccines using various technological platforms. For example, researchers led by Roy Curtiss 3rd have developed a new approach to achieve controlled, delayed attenuation of bacterial pathogens. Mutants generated using this method were superior in protecting Y. pestis-infected mice immunized with strains generated using traditional gene knockout. However, further studies are needed to determine the safety and efficacy of these delayed-attenuated strains in other mammalian species in order to extrapolate on humans the data obtained in accordance with the FDA Animal Rule. Three Y. pestis strains, a Δcrp mutant, a mutant with arabinose-dependent regulated crp expression (araC P_BAD crp) or an araC P_BAD crp mutant cured of plasmid pPst were derived from virulent wild-type strain 231. To evaluate the safety, outbred mice or guinea pigs were immunized subcutaneously with serial tenfold dilutions of mutated strains. For vaccine studies, immunized animals were subcutaneously challenged with 200 LD₁₀₀ (lethal dose in all exposed subjects) of the wild-type Y. pestis strain. The challenge caused the death of 100% of naïve animals in controls. The Y. pestis strain 231Δcrp was nonlethal in mice at a dose of 10⁷ CFs. The LD₅₀ of the 231Δcrp strain in guinea pigs increased by at least 10⁷-fold compared to that of the wild-type strain. The LD₅₀s of the 231P_BAD-crp mutant in mice and guinea pigs were approximately 10⁴-fold and 10⁷-fold higher than those of Y. pestis 231, respectively. The 231P_BAD-crp(pPst¯) strain did not cause death in mice (LD₅₀ > 10⁷ CFU) and guinea pigs (LD₅₀ > 10⁹ CFU) when administered subcutaneously and was capable of inducing intense protective immunity in both species of laboratory animals. Our research has shown once again the necessity of balance between safety and effectiveness demonstrating the feasibility of further investigation of crp mutants as promising candidate plague vaccines.

Keywords: Yersinia pestis; Crp; regulated delayed attenuation; crp; plague vaccine; protection

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MDPI and ACS Style

Dentovskaya, S.V.; Shaikhutdinova, R.Z.; Platonov, M.E.; Lipatnikova, N.A.; Mazurina, E.M.; Gapel’chenkova, T.V.; Kopylov, P.K.; Ivanov, S.A.; Trunyakova, A.S.; Vagaiskaya, A.S.; et al. Virulence Reduction in Yersinia pestis by Combining Delayed Attenuation with Plasmid Curing. Biomolecules 2026, 16, 40. https://doi.org/10.3390/biom16010040

AMA Style

Dentovskaya SV, Shaikhutdinova RZ, Platonov ME, Lipatnikova NA, Mazurina EM, Gapel’chenkova TV, Kopylov PK, Ivanov SA, Trunyakova AS, Vagaiskaya AS, et al. Virulence Reduction in Yersinia pestis by Combining Delayed Attenuation with Plasmid Curing. Biomolecules. 2026; 16(1):40. https://doi.org/10.3390/biom16010040

Chicago/Turabian Style

Dentovskaya, Svetlana V., Rima Z. Shaikhutdinova, Mikhail E. Platonov, Nadezhda A. Lipatnikova, Elizaveta M. Mazurina, Tat’yana V. Gapel’chenkova, Pavel Kh. Kopylov, Sergei A. Ivanov, Alexandra S. Trunyakova, Anastasia S. Vagaiskaya, and et al. 2026. "Virulence Reduction in Yersinia pestis by Combining Delayed Attenuation with Plasmid Curing" Biomolecules 16, no. 1: 40. https://doi.org/10.3390/biom16010040

APA Style

Dentovskaya, S. V., Shaikhutdinova, R. Z., Platonov, M. E., Lipatnikova, N. A., Mazurina, E. M., Gapel’chenkova, T. V., Kopylov, P. K., Ivanov, S. A., Trunyakova, A. S., Vagaiskaya, A. S., & Anisimov, A. P. (2026). Virulence Reduction in Yersinia pestis by Combining Delayed Attenuation with Plasmid Curing. Biomolecules, 16(1), 40. https://doi.org/10.3390/biom16010040

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Virulence Reduction in Yersinia pestis by Combining Delayed Attenuation with Plasmid Curing

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