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Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response

Nature Immunology volume 7, pages 1066–1073 (2006)Cite this article

Abstract

At mammalian body temperature, the plague bacillus Yersinia pestis synthesizes lipopolysaccharide (LPS)–lipid A with poor Toll-like receptor 4 (TLR4)–stimulating activity. To address the effect of weak TLR4 stimulation on virulence, we modified Y. pestis to produce a potent TLR4-stimulating LPS. Modified Y. pestis was completely avirulent after subcutaneous infection even at high challenge doses. Resistance to disease required TLR4, the adaptor protein MyD88 and coreceptor MD-2 and was considerably enhanced by CD14 and the adaptor Mal. Both innate and adaptive responses were required for sterilizing immunity against the modified strain, and convalescent mice were protected from both subcutaneous and respiratory challenge with wild-type Y. pestis. Despite the presence of other established immune evasion mechanisms, the modified Y. pestis was unable to cause systemic disease, demonstrating that the ability to evade the LPS-induced inflammatory response is critical for Y. pestis virulence. Evading TLR4 activation by lipid A alteration may contribute to the virulence of various Gram-negative bacteria.

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Figure 1: LPS from Y. pestis grown at 37 °C has inhibitory activity.
Figure 2: Y. pestis pLpxL synthesizes a potent LPS.
Figure 3: Y. pestis pLpxL is avirulent in wild-type mice.
Figure 4: MyD88, Mal and CD14 contribute to the LPS-mediated survival of mice infected with KIM1001-pLpxL.
Figure 5: Y. pestis with potent TLR4-activating ability is an effective vaccine against plague.
Figure 6: Adaptive immunity is critical for protection against KIM1001-pLpxL.

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Acknowledgements

We thank A. Yuan, N. Pan and K. Trimble for help with experiments; N. Deitemeyer and C. Lee for technical assistance; A. Cerny and J. Boulangier for animal husbandry; D.T. Golenbock for support; and R.R. Ingalls, N. Silverman and K. Fitzgerald for critically reading the manuscript. Supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01 AI057588 to E.L.) and the Diabetes Endocrinology Research Center (DK 32520).

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Authors and Affiliations

  1. Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, 01605, Massachusetts, USA

    Sara W Montminy, Naseema Khan, Fiona Sharp, Joseph E Conlon, Charles Sweet & Egil Lien

  2. Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Sara McGrath & Robert J Cotter

  3. Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, 01655, Massachusetts, USA

    Mitchell J Walkowicz & Jon D Goguen

  4. Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, 560-0043, Japan

    Koichi Fukase & Shoichi Kusumoto

  5. Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan

    Kensuke Miyake

  6. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, 565-0871, Japan

    Shizuo Akira

Authors
  1. Sara W Montminy
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Corresponding author

Correspondence to Egil Lien.

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A patent has been filed concerning the use of modified bacterial strains as vaccines.

Supplementary information

Supplementary Fig. 1

Y. pestis grown at 37 °C is a poor stimulator of TLR4 signaling. (PDF 75 kb)

Supplementary Fig. 2

Y. pestis 37 °C LPS inhibits activation of non-human primate cells by 26 °C LPS. (PDF 51 kb)

Supplementary Fig. 3

Mass spectrometry analysis of lipid A from Y. pestis KIM5 and KIM5-pLpxL grown at 26 °C or 37 °C. (PDF 465 kb)

Supplementary Fig. 4

Non-human primate cells respond to LPS from Y. pestis KIM5-pLpxL grown at both 26 °C and 37 °C. (PDF 64 kb)

Supplementary Fig. 5

Y. pestis containing pLpxL retains key features. (PDF 132 kb)

Supplementary Fig. 6

The presence of plasmid vector does not affect KIM1001 virulence. (PDF 51 kb)

Supplementary Fig. 7

Y. pestis KIM1001-pLpxL IV infection is associated with increased survivial times. (PDF 56 kb)

Supplementary Fig. 8

Y. pestis and Y. pestis-pLpxL generate a rough form of LPS. (PDF 71 kb)

Supplementary Methods (PDF 90 kb)

Supplementary Note (PDF 91 kb)

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Montminy, S., Khan, N., McGrath, S. et al. Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response. Nat Immunol 7, 1066–1073 (2006). https://doi.org/10.1038/ni1386

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