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


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.

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Figure 1: Structural modifications in lipid A from E. coli (EC), Rhodobacter sphaeroides (RS) and Pseudomonas aeruginosa (PA).
Figure 2: TLR4 mediates species-specific recognition of CF LPS.
Figure 3: mTLR4, in conjunction with either mMD-2 or hMD-2, mediates recognition of penta-acylated LPS.
Figure 4: A hypervariable region of the TLR4 extracellular domain evolved across species.
Figure 5: The hypervariable region of the murine TLR4 middle domain is required for recognition of penta-acylated LPS.
Figure 6: MD-2 is essential in the discrimination of lipidIVA and taxol but not PA LPS.

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We thank D. T. Golenbock for lipidIVA and RS lipid A; R. Medzhitov for the hTLR4 construct; K. Miyake for the MD-2 constructs; A. Perchellet for help with preparing the hCD14 construct; and E. Sokurenko for suggestions. Supported by grants from the CF Foundation (R565-Wilson) and from the NIH (HL69503-Hajjar, HL65898-Wilson and AI47938-Miller).

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Correspondence to Christopher B. Wilson or Samuel I. Miller.

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Hajjar, A., Ernst, R., Tsai, J. et al. Human Toll-like receptor 4 recognizes host-specific LPS modifications. Nat Immunol 3, 354–359 (2002).

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