Virulence factors of Yersinia pestis are overcome by a strong lipopolysaccharide response.
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.
Montminy
Sara W
SW
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Khan
Naseema
N
McGrath
Sara
S
Walkowicz
Mitchell J
MJ
Sharp
Fiona
F
Conlon
Joseph E
JE
Fukase
Koichi
K
Kusumoto
Shoichi
S
Sweet
Charles
C
Miyake
Kensuke
K
Akira
Shizuo
S
Cotter
Robert J
RJ
Goguen
Jon D
JD
Lien
Egil
E
D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008050:Lipid A / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D010930:Plague / Q000517:prevention & control*; D010931:Plague Vaccine / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000037:antagonists & inhibitors; D014611:Vaccination; D014774:Virulence / Q000276:immunology; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D015010:Yersinia pestis / Q000276:immunology* / Q000472:pathogenicity
D029968:Escherichia coli Proteins; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D010931:Plague Vaccine; D051197:Toll-Like Receptor 4; D037521:Virulence Factors; D000217:Acyltransferases; C492237:LpxL protein, E coli