Nature Immunology
- 7, 1066 - 1073 (2006)
Published online: 17 September 2006; | doi:10.1038/ni1386
Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide responseSara W Montminy1, Naseema Khan1, Sara McGrath2, Mitchell J Walkowicz3, Fiona Sharp1, Joseph E Conlon1, Koichi Fukase4, Shoichi Kusumoto4, Charles Sweet1, Kensuke Miyake5, Shizuo Akira6, Robert J Cotter2, Jon D Goguen3 & Egil Lien11
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. 2
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. 3
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA. 4
Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka 560-0043, Japan. 5
Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. 6
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
Correspondence should be addressed to Egil Lien egil.lien@umassmed.edu 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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