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Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity

Nature Medicine volume 16, pages 228231 (2010) | Download Citation


Humans are colonized by a large and diverse bacterial flora (the microbiota) essential for the development of the gut immune system1,2,3. A broader role for the microbiota as a major modulator of systemic immunity has been proposed4,5; however, evidence and a mechanism for this role have remained elusive. We show that the microbiota are a source of peptidoglycan that systemically primes the innate immune system, enhancing killing by bone marrow–derived neutrophils of two major pathogens: Streptococcus pneumoniae and Staphylococcus aureus. This requires signaling via the pattern recognition receptor nucleotide-binding, oligomerization domain–containing protein-1 (Nod1, which recognizes meso-diaminopimelic acid (mesoDAP)-containing peptidoglycan found predominantly in Gram-negative bacteria), but not Nod2 (which detects peptidoglycan found in Gram-positive and Gram-negative bacteria) or Toll-like receptor 4 (Tlr4, which recognizes lipopolysaccharide)6,7. We show translocation of peptidoglycan from the gut to neutrophils in the bone marrow and show that peptidoglycan concentrations in sera correlate with neutrophil function. In vivo administration of Nod1 ligands is sufficient to restore neutrophil function after microbiota depletion. Nod1−/− mice are more susceptible than wild-type mice to early pneumococcal sepsis, demonstrating a role for Nod1 in priming innate defenses facilitating a rapid response to infection. These data establish a mechanism for systemic immunomodulation by the microbiota and highlight potential adverse consequences of microbiota disruption by broad-spectrum antibiotics on innate immune defense to infection.

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  1. 1.

    Microbial ecology of the gastrointestinal tract. Annu. Rev. Microbiol. 31, 107–133 (1977).

  2. 2.

    , & Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124, 837–848 (2006).

  3. 3.

    Immune responses to commensal and environmental microbes. Nat. Immunol. 8, 1173–1178 (2007).

  4. 4.

    & Does the microbiota regulate immune responses outside the gut? Trends Microbiol. 12, 562–568 (2004).

  5. 5.

    & The 'microflora hypothesis' of allergic diseases. Clin. Exp. Allergy 35, 1511–1520 (2005).

  6. 6.

    , & Intracellular NOD-like receptors in host defense and disease. Immunity 27, 549–559 (2007).

  7. 7.

    & Toll-like receptors and their ligands. Curr. Top. Microbiol. Immunol. 270, 81–92 (2002).

  8. 8.

    & The love-hate relationship between bacterial polysaccharides and the host immune system. Nat. Rev. Immunol. 6, 849–858 (2006).

  9. 9.

    , , , & Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).

  10. 10.

    et al. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses. Immunity 29, 637–649 (2008).

  11. 11.

    et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nat. Immunol. 9, 769–776 (2008).

  12. 12.

    , , & An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).

  13. 13.

    & Interactions between commensal intestinal bacteria and the immune system. Nat. Rev. Immunol. 4, 478–485 (2004).

  14. 14.

    How neutrophils kill microbes. Annu. Rev. Immunol. 23, 197–223 (2005).

  15. 15.

    et al. Nod1 signaling overcomes resistance of S. pneumoniae to opsonophagocytic killing. PLoS Pathog. 3, e118 (2007).

  16. 16.

    & Human neutrophils kill Streptococcus pneumoniae via serine proteases. J. Immunol. 183, 2602–2609 (2009).

  17. 17.

    et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat. Med. 12, 1365–1371 (2006).

  18. 18.

    , , , & Intestinal permeability and the prediction of relapse in Crohn's disease. Lancet 341, 1437–1439 (1993).

  19. 19.

    et al. Bacterial peptide recognition and immune activation facilitated by human peptide transporter PEPT2. Am. J. Respir. Cell Mol. Biol. 39, 536–542 (2008).

  20. 20.

    et al. hPepT1 selectively transports muramyl dipeptide but not Nod1-activating muramyl peptides. Can. J. Physiol. Pharmacol. 84, 1313–1319 (2006).

  21. 21.

    , , , & Neutrophil-toxin interactions promote antigen delivery and mucosal clearance of Streptococcus pneumoniae. J. Immunol. 180, 6246–6254 (2008).

  22. 22.

    , , & Clinical detection of LPS and animal models of endotoxemia. Immunobiology 187, 330–345 (1993).

  23. 23.

    et al. Bacterial peptidoglycan triggers Candida albicans hyphal growth by directly activating the adenylyl cyclase Cyr1p. Cell Host Microbe 4, 28–39 (2008).

  24. 24.

    et al. Peptidoglycans as promoters of slow-wave sleep. II. Somnogenic and pyrogenic activities of some naturally occurring muramyl peptides; correlations with mass spectrometric structure determination. J. Biol. Chem. 259, 12659–12662 (1984).

  25. 25.

    Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).

  26. 26.

    , & Clostridium difficile colitis. N. Engl. J. Med. 330, 257–262 (1994).

  27. 27.

    , & Live attenuated Streptococcus pneumoniae strains induce serotype-independent mucosal and systemic protection in mice. Infect. Immun. 75, 2469–2475 (2007).

  28. 28.

    et al. Immunoactive peptides, FK-156 and FK-565. III. Enhancement of host defense mechanisms against infection. J. Antibiot. (Tokyo) 36, 1059–1066 (1983).

  29. 29.

    et al. Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-κB. J. Biol. Chem. 274, 14560–14567 (1999).

  30. 30.

    , , & Role for erbin in bacterial activation of Nod2. Infect. Immun. 74, 3115–3124 (2006).

  31. 31.

    et al. Mutational analysis of the substrate specificity of Escherichia coli penicillin binding protein 4. Biochemistry 48, 2675–2683 (2009).

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We thank C.G. Dowson and D.I. Roper (University of Warwick) for peptidoglycan fragments, D. J. Philpott (University of Toronto) for Nod vector, and D. Kobuley for assistance with germ-free mice. This work was supported by grants AI038446 (J.N.W.), AI044231 (J.N.W.), AI078538 (J.N.W.) and AI037108 (Y.Y.) from the US Public Health Service.

Author information


  1. Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Thomas B Clarke
    • , Kimberly M Davis
    • , Elena S Lysenko
    • , Alice Y Zhou
    •  & Jeffrey N Weiser
  2. Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Yimin Yu
  3. Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Jeffrey N Weiser


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T.B.C. designed the research, performed the experiments, analyzed the data and wrote the manuscript; K.M.D. performed experiments, analyzed data and contributed to the manuscript; E.S.L. and A.Y.Z. performed experiments and analyzed data; Y.Y. contributed vital reagents; and J.N.W. designed the research, analyzed the data and wrote the manuscript.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Jeffrey N Weiser.

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