Human Toll-like receptor 4 recognizes host-specific LPS modifications

Nat Immunol. 2002 Apr;3(4):354-9. doi: 10.1038/ni777. Epub 2002 Mar 25.


Lipopolysaccharide (LPS) is the principal proinflammatory component of the Gram-negative bacterial envelope and is recognized by the Toll-like receptor 4 (TLR4)-MD-2 receptor complex. Bacteria can alter the acylation state of their LPS in response to environmental changes. One opportunistic bacterium, Pseudomonas aeruginosa, synthesizes more highly acylated (hexa-acylated) LPS structures during adaptation to the cystic fibrosis airway. Here we show that human, but not murine, TLR4-MD-2 recognizes this adaptation and transmits robust proinflammatory signals in response to hexa-acylated but not penta-acylated LPS from P. aeruginosa. Whereas responses to lipidIVA and taxol are dependent on murine MD-2, discrimination of P. aeruginosa LPS structures is mediated by an 82-amino-acid region of human TLR4 that is hypervariable across species. Thus, in contrast to mice, humans use TLR4 to recognize a molecular signature of bacterial-host adaptation to modulate the innate immune response.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, Surface / genetics
  • Antigens, Surface / immunology*
  • Binding Sites
  • Carbohydrate Sequence
  • Cell Differentiation
  • Cell Line
  • Drosophila Proteins*
  • Humans
  • Infant
  • Lipid A / chemistry
  • Lipid A / immunology*
  • Lymphocyte Antigen 96
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Mice
  • Molecular Sequence Data
  • Pseudomonas aeruginosa / immunology
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology*
  • Toll-Like Receptor 4
  • Toll-Like Receptors


  • Antigens, Surface
  • Drosophila Proteins
  • LY96 protein, human
  • Lipid A
  • Lymphocyte Antigen 96
  • Membrane Glycoproteins
  • Receptors, Cell Surface
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptors

Associated data

  • GENBANK/AF057025