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

Nature Immunology volume 3, pages 354–359 (2002)Cite this article

Abstract

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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Acknowledgements

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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Author notes

  1. Adeline M. Hajjar and Robert K. Ernst: These authors contributed equally to this work.

  2. Christopher B. Wilson and Samuel I. Miller: These authors share senior authorship.

Authors and Affiliations

  1. Department of Immunology, University of Washington, Seattle, 98195, WA, USA

    Adeline M. Hajjar, Jeff H. Tsai & Christopher B. Wilson

  2. Department of Microbiology, University of Washington, Seattle, 98195, WA, USA

    Robert K. Ernst & Samuel I. Miller

  3. Department of Pediatrics, University of Washington, Seattle, 98195, WA, USA

    Christopher B. Wilson

  4. Department of Medicine, University of Washington, Seattle, 98195, WA, USA

    Samuel I. Miller

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  1. Adeline M. Hajjar
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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). https://doi.org/10.1038/ni777

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