Review Article | Published:

LPS, TLR4 and infectious disease diversity

Nature Reviews Microbiology volume 3, pages 3646 (2005) | Download Citation

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Abstract

Innate immune receptors recognize microorganism-specific motifs. One such receptor–ligand complex is formed between the mammalian Toll-like receptor 4 (TLR4)–MD2–CD14 complex and bacterial lipopolysaccharide (LPS). Recent research indicates that there is significant phylogenetic and individual diversity in TLR4-mediated responses. In addition, the diversity of LPS structures and the differential recognition of these structures by TLR4 have been associated with several bacterial diseases. This review will examine the hypothesis that the variability of bacterial ligands such as LPS and their innate immune receptors is an important factor in determining the outcome of infectious disease.

Key points

  • A central question in infectious disease research is how the complex interplay between host and pathogen determines the outcome of infection. This article discusses a mechanism by which variability in innate immune receptors (such as Toll-like receptors, TLRs) and their bacterial ligands (such as LPS) could explain why individual members of a host population exhibit variable disease outcome.

  • Susceptibility to bacterial infection varies greatly in different members of a host population. For example, polymorphisms in innate immune genes in Drosophila have been identified and are linked to disease susceptibility. In addition, bacterial type III effectors of the plant pathogen Pseudomonas syringae show great variability in recognition by plant innate immunity.

  • In humans, polymorphisms in TLRs have been shown to be associated with a variety of diseases.

  • Lipid A is the sole portion of LPS recognized by TLR4. Lipid A is not a single molecule, but shows great diversity among different bacteria. Many lipid A structural differences are environmentally regulated by bacterial signal transduction systems, such as PhoP–PhoQ, which is highly conserved among human, plant and insect pathogens.

  • Many regulated lipid A modifications are required for bacterial virulence. For example, lipid A modifications promote virulence in a variety of pathogens including Salmonella enterica serovar Typhimurium, Legionella pneumophilia, Bordetella bronchiseptica, the insect pathogen Photorhabdus luminescens and the plant pathogen Erwinia carotovora. In many cases, lipid A modifications promote bacterial resistance to killing by antimicrobial peptides.

  • Different lipid A structures exhibit differential recognition by TLR4. Recognition of lipid A is in part determined by extracellular variable domains in TLR4 and MD2. There is evidence for positive selection in these domains across different species, which supports the hypothesis that variability in innate immune recognition determines infectious disease outcome.

  • Lipid A structures are associated with human disease. Pseudomonas aeruginosa isolated from cystic fibrosis patients exhibit lipid A structures that are not found in environmental isolates.

  • When grown at 37°C, Yersinia pestis, the causative agent of plague, is not recognized by human TLR4 but is recognized by mouse TLR4. A general principle of highly virulent Gram-negative pathogens is that recognition of lipid A may be reduced. This property of Y. pestis is not present in Yersinia pseudotuberculosis, from which Y. pestis evolved, and mighty indicate co-evolution of lipid A structure with alteration in host range (insects) and increasing human virulence.

  • Innate immune stimulants and modifiers derived from lipid A may have important utility in the future to protect against infectious diseases.

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Acknowledgements

We would like to thank T. Freeman for calculating the synonymous/non-synonymous content of TLR4 and MD2. We thank C. Wilson and members of the Miller lab for helpful discussions. The authors were supported by grants from the NIAID, and Cystic Fibrosis Foundation grants to S.I.M., a NIH grant to R.K.E and an Emmy-Noether fellowship from Deutsche Forschungsgemeinschaft to M.W.B. S.I.M. and R.K.E. were funded by the NIAID Research Centre for Excellence in Biodefense and Emerging Infectious Diseases.

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  1. Department of Medicine, University of Washington Medical School, Seattle, Washington 98195, USA.

    • Samuel I. Miller
    •  & Robert K. Ernst
  2. Department of Microbiology, University of Washington Medical School, Seattle, Washington 98195, USA.

    • Samuel I. Miller
  3. Department of Genome Sciences, University of Washington Medical School, Seattle, Washington 98195, USA.

    • Samuel I. Miller
    •  & Martin W. Bader

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Correspondence to Samuel I. Miller.

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