A live attenuated strain of Yersinia pestis KIM as a vaccine against plague

Wei Sun, David Six, Xiaoying Kuang, Kenneth L. Roland, Christian R H Raetz, Roy Curtiss

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Yersinia pestis, the causative agent of plague, is a potential weapon of bioterrorism. Y. pestis evades the innate immune system by synthesizing tetra-acylated lipid A with poor Toll-like receptor 4 (TLR4)-stimulating activity at 37°C, whereas hexa-acylated lipid A, a potent TLR4 agonist, is made at lower temperatures. Synthesis of Escherichia coli LpxL, which transfers the secondary laurate chain to the 2'-position of lipid A, in Y. pestis results in production of hexa-acylated lipid A at 37°C, leading to significant attenuation of virulence. Previously, we described a Y. pestis vaccine strain in which crp expression is under the control of the arabinose-regulated araC PBAD promoter, resulting in a 4-5 log reduction in virulence. To reduce the virulence of the crp promoter mutant further, we introduced E. coli lpxL into the Y. pestis chromosome. The χ10030(pCD1Ap) (ΔlpxP32::PlpxL lpxL ΔPcrp21::TT araC PBAD crp) construct likewise produced hexa-acylated lipid A at 37°C and was significantly more attenuated than strains harboring each individual mutation. The LD50 of the mutant in mice, when administered subcutaneously or intranasally was >107-times and >104-times greater than wild type, respectively. Mice immunized subcutaneously with a single dose of the mutant were completely protected against a subcutaneous challenge of 3.6×107 wild-type Y. pestis and significantly protected (80% survival) against a pulmonary challenge of 1.2×104 live cells. Intranasal immunization also provided significant protection against challenges by both routes. This mutant is an immunogenic, highly attenuated live Y. pestis construct that merits further development as a vaccine candidate.

Original languageEnglish (US)
Pages (from-to)2986-2998
Number of pages13
JournalVaccine
Volume29
Issue number16
DOIs
StatePublished - Apr 5 2011

Keywords

  • Lipid A
  • Plague vaccine
  • Regulated delayed attenuation
  • Yersinia pestis

ASJC Scopus subject areas

  • Molecular Medicine
  • Immunology and Microbiology(all)
  • veterinary(all)
  • Public Health, Environmental and Occupational Health
  • Infectious Diseases

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  • Cite this

    Sun, W., Six, D., Kuang, X., Roland, K. L., Raetz, C. R. H., & Curtiss, R. (2011). A live attenuated strain of Yersinia pestis KIM as a vaccine against plague. Vaccine, 29(16), 2986-2998. https://doi.org/10.1016/j.vaccine.2011.01.099