• Peptidoglycan;
  • Innate immunity;
  • Drosophila;
  • Toll-like receptors;
  • Nod


  1. Top of page
  2. Abstract
  3. 1 Introduction
  4. 2 Study of the role of peptidoglycan in innate immunity during the pre-Toll/TLR/ Nod era
  5. 3 Peptidoglycan triggers innate immune responses in Drosophila
  6. 4 Peptidoglycan detection in mammals
  7. 5 Conclusions

The importance of peptidoglycan detection in the host innate immune response has long been underestimated. However, the recent identification of proteins involved in the sensing of peptidoglycan in both mammals and Drosophila has revealed that the detection of this microbial motif is key to the defense response. In Drosophila, the peptidoglycan-recognition proteins (PGRP) are the initial sensors of infecting bacteria that then trigger a cascade ultimately leading to the expression of antimicrobial peptides. In mammals, PGRP also exist and although they bind peptidoglycan, the role of these proteins in innate immune responses remains to be clearly defined. In contrast, the Nod proteins (Nod1 and Nod2), which are also involved in peptidoglycan sensing, appear to play a key role in innate immunity against bacteria by triggering host defense responses through the activation of the transcription factor, NF-κB. Interstingly, mutations in Nod2 are related to increased susceptibility to Crohn's disease, thereby implicating defective bacterial sensing in the development at this chronic disease. In this review, we will focus on the recent findings concerning mammalian and Drosophila proteins involved in peptidoglycan recognition and the putative role of these proteins in the innate immune defense response.

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Bacterial lipoprotein


Diaminopimelic acid


Immune deficiency


Lipoteichoic acid




Pathogen-associated molecular pattern


Peptidoglycan-recognition protein


Toll-like receptor

1 Introduction

  1. Top of page
  2. Abstract
  3. 1 Introduction
  4. 2 Study of the role of peptidoglycan in innate immunity during the pre-Toll/TLR/ Nod era
  5. 3 Peptidoglycan triggers innate immune responses in Drosophila
  6. 4 Peptidoglycan detection in mammals
  7. 5 Conclusions

Innate immunity is the most ancient and common system in the animal kingdom for defense against microbial infection. Whereas adaptive immunity is found only in vertebrates, innate immunity is conserved in all animals throughout evolution 1. There are multiple characteristics that allow us to distinguish between innate and adaptive immunity, but the means used to detectthe intruder represent a major difference between the two arms of the immune system. Indeed, the innate immune system detects microbes through a limited set of receptors encoded by the germinal lineage, and this system does not keep a record (or memory) of former microbes encountered, as is observed in the adaptive immune system. As a consequence, Charles Janeway proposed that the innate immune system would probably have evolved detection systems against microbial signatures that remain invariant inside a class of microbes, as opposed to antigens that can vary into infinite combinations 1.

Examples of such microbial motifs, now also known as pathogen-associated molecular patterns (PAMP), include structural molecules from the bacterial cell wall that are absent from the host: LPS, bacterial lipoproteins (BLP), lipoteichoic acid (LTA), teichoic acid, peptidoglycan and flagellin. Other PAMP are found among the microbial genetic storage system: CpG DNA for bacteria, and double-stranded or single-stranded RNA for some viruses. The prediction of Janeway has been verified in a spectacular way with the discovery of Toll-like receptors (TLR) in mammals. Indeed, for every PAMP listed above there is a corresponding, unique TLR on the host's side that can initiate a defense response following detection of its corresponding microbial motif (see 2 for review).

In the past few years, a large number of reviews have focused on TLR and the role of this family of receptors in innate immunity. In contrast, the aim of this review is to put the emphasis on peptidoglycan, a bacterial PAMP whose contribution to generating the innate immune response remains widely unknown and perhaps underestimated as compared with LPS, for example. However, with the recent discovery of the Nods — a new family of intracellular PAMP sensors involved in peptidoglycan detection — and of the peptidoglycan-recognition proteins (PGRP) in mammals and Drosophila, the contribution of peptidoglycan to the global innate immune response can now be revisited.

2 Study of the role of peptidoglycan in innate immunity during the pre-Toll/TLR/ Nod era

  1. Top of page
  2. Abstract
  3. 1 Introduction
  4. 2 Study of the role of peptidoglycan in innate immunity during the pre-Toll/TLR/ Nod era
  5. 3 Peptidoglycan triggers innate immune responses in Drosophila
  6. 4 Peptidoglycan detection in mammals
  7. 5 Conclusions

The pro-inflammatory properties of peptidoglycan have long been studied using various animal and cellular models. The initial observations had shown that peptidoglycan from Gram-positive bacterial cell wall induces inflammation following injection into the peritoneal cavity of rats 3. The inflammation is characterized by accumulation of peptidoglycan within synovial and periarticular tissues, associated with destruction of the joints. In addition, peptidoglycan from Gram-positive bacteria induces meningeal inflammation in rabbits injected intracisternally 4. In cell culture models, early reports identified the immunomodulatory properties of peptidoglycan and/or subfragments of peptidoglycan towards monocytes, macrophages 5, 6, neutrophils 7 and respiratory epithelial cells 8. Pro-inflammatory cytokines such as IL-1, IL-6 and TNF-α are known to be released by macrophages following exposure to either Gram-positive bacterial peptidoglycan or soluble muramyl peptides derived from polymeric peptidoglycan (for a review, see 9).

These initial studies paved the way to the characterization of the pro-inflammatory properties of peptidoglycan. However, this field of investigation was hampered by two major limitations: (i) the absence of identification of the molecular sensors responsible for the detection of peptidoglycan by the innate immune system, and (ii) the difficulty of purification of peptidoglycan, which has resulted in confusion between immunological properties of peptidoglycan per se, and of macromolecules associated with peptidoglycan, such as LTA or lipoproteins.

3 Peptidoglycan triggers innate immune responses in Drosophila

  1. Top of page
  2. Abstract
  3. 1 Introduction
  4. 2 Study of the role of peptidoglycan in innate immunity during the pre-Toll/TLR/ Nod era
  5. 3 Peptidoglycan triggers innate immune responses in Drosophila
  6. 4 Peptidoglycan detection in mammals
  7. 5 Conclusions

Drosophila has long been a key model for studying the innate immune system in animals. The fat-body of the larva responds to pathogen aggression by inducing anti-microbial peptides such as Diptericin, Drosomycin, Metchnikowin or Attacin (for a review, see 10). During the last decade, the study of signaling pathways that lead to the induction of anti-microbial peptides following infection has received considerable attention. The seminal discovery was the implication of Toll, a membrane-anchored protein previously known for its function during development 11, as a key protein involved in innate immune defense against fungal infection 12. Subsequently, two major signaling pathways have been identified — Toll and immune deficiency (Imd) 12, 13. The Toll signaling pathway is activated by fungi and Gram-positive bacteria, leading to the induction of anti-microbial peptides such as Drosomycin (Fig. 1). In contrast, the Imd pathway is triggered specifically following infection with Gram-negative bacteria, and results in the induction of a different set of anti-microbial peptides, such as Diptericin (Fig. 1).

While most of the attention was focused on the characterization of the network of factors involved in signal transduction, little was known about the microbial motifs responsible for the initial triggering of either the Toll or the Imd pathway. Recently, fundamental observations have been made, allowing a better understanding of how PAMP specifically induce either Toll or Imd signaling. First, genetic evidence has demonstrated that PGRP are upstream intermediates in the signaling pathways leading to the activation of Toll or Imd. Indeed, PGRP-SA (together with GNBP1) is required for the induction of Toll following Gram-positive bacterial infection 1416, whereas the response to Gram-negative bacteria is mediated by PGRP-LC 1719.

PGRP are proteins that were isolated due to their ability to interact with peptidoglycan with high affinity; they were identified first in the silkworm Bombyx mori and then homologs were found in Drosophila and mammals 20. Therefore, the identification of PGRP as key factors involved in the activation of the innate immune response in Drosophila strongly suggested that peptidoglycan was the PAMP specifically detected by the host to induce Toll and Imd signaling. This hypothesis was brought to light recently by Leulier et al., who also provided evidence that Drosophila distinguish between Gram-negative and Gram-positive bacterial infections directly at the level of peptidoglycan detection 21 (Fig. 1). It was known for decades that whereas a lysine (LYS) residue is found in third position of the peptidoglycan stem peptide in most Gram-positive bacteria, an unusual amino acid — meso-diaminopimelic acid (DAP) — replaces lysine in Gram-negative bacteria 22. This subtle difference is used by the Drosophila innate immune system to distinguish between classes of bacterial pathogens. Indeed, the Imd pathway is activated following detection of DAP-type peptidoglycan by PGRP-LC, whereas PGRP-SA activates the Toll pathway following sensing of LYS-type peptidoglycan 21 (Fig. 1).

How PGRP-LC and PGRP-SA trigger the activation of Imd and Toll, respectively, following detection of peptidoglycan remains unknown. Since these proteins do not display enzymatic activity, signal transduction could be initiated following either conformational change of the molecules or ligand-dependent clustering. A first piece of evidence towards the elucidation of this question came from the analysis of the structure of Drosophila PGRP-LB, another protein of the PGRP family whose function in innate immunity remains unknown 23. Upon interaction with peptidoglycan, PGRP-LB forms a multimeric complex that exposes a surface potentially recruiting downstream effector(s); this mechanism may follow an induced-proximity model 23. By analogy, such a mechanism could also be responsible for the activation of signaling pathways downstream of PGRP-SA and PGRP-LC.

Apart from PGRP-SA and PGRP-LC, 11 other PGRP are found within the Drosophila genome 20. Since these PGRP have been identified by the presence of a so-called PGRP domain, all these proteins can potentially contribute to innate immunity through their ability to interact with peptidoglycan. However, temporal expression, tissue distribution and function remain unknown for most PGRP. A notable exception is PGRP-SC1B, a soluble protein that has been shown to display catalytic activity towards peptidoglycan: the protein hydrolyses the bond between the MurNAc sugar moiety and the stem peptide, a cleavage characteristic of a class of enzymes called N-acetylmuramoyl-L-alanine amidases, which also includes mammalian PGRP-L (24, 25; see below). Because PGRP-SC1B degrades peptidoglycan, the molecule is believed to display a scavenger function allowing the termination of the anti-microbial reaction following clearance of the bacterial intruder 24. Finally, PGRP-LE is another PGRP that, like PGRP-LC, is able to specifically detect DAP-type peptidoglycan and to activate both the Imd pathway and the prophenoloxidase cascade 26. However, the precise interplay between PGPR-LC and PGRP-LE still remains unknown.

These findings have brought to the forefront the importance of peptidoglycan recognition as a key event in the specific activation of anti-microbial signaling pathways in Drosophila immunity. The differences in peptidoglycan structure between Gram-negative and Gram-positive bacteria stimulate specific anti-bacterial responses through the Imd and Toll pathway, respectively. Remarkably, these recent discoveries seem to rule out any significant contribution of other microbial motifs, including LPS, LTA, etc., to the production of anti-microbial peptides. However, it remains to be defined whether these motifs may be involved in alternative innate immune responses during different developmental stages of the fly.

4 Peptidoglycan detection in mammals

  1. Top of page
  2. Abstract
  3. 1 Introduction
  4. 2 Study of the role of peptidoglycan in innate immunity during the pre-Toll/TLR/ Nod era
  5. 3 Peptidoglycan triggers innate immune responses in Drosophila
  6. 4 Peptidoglycan detection in mammals
  7. 5 Conclusions

4.1 PGRP and Nod proteins trigger innate immune responses

Peptidoglycan recognition is also key in generating the innate immune response in mammals (Fig. 1). Two families of proteins mediate peptidoglycan recognition — these are the PGRP and Nod proteins. Whereas the Nod proteins — Nod1 and Nod2 — are cytoplasmic proteins, mammalian PGRP likely detect peptidoglycan in different cellular or tissue compartments owing to the fact that they are membrane-bound, stored in vesicles, or secreted proteins.

thumbnail image

Figure 1. Innate immune recognition of peptidoglycan by mammals (left) and Drosophila (right) relies on specific detection of DAP-type or LYS-type peptidoglycans (PGN). In mammals, Nod1 and Nod2 mediate the recognition of these PGN structures through pathways that are independent of TLR; examples PAMP that are known to be recognized by specific TLR molecules are shown. In Drosophila, DAP-type PGN is detected by PGRP-LC, which stimulates the Imd pathway, leading to the production of antimicrobial peptides including Diptericin. LYS-type peptidoglycan, on the other hand, is recognized by PGRP-SA that is complexed to GNBP1, leading to Spätzle-dependent activation of Toll and expression of anti-microbial peptides including Drosomycin. Other Drosophila PGRP could play a role in peptidoglycan detection, for example PGRP-SC1B, which displays lytic activity towards peptidoglycan and therefore is likely to play a scavenger function.

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4.2 Mammalian PGRP

There are four PGRP present in humans — PGRP-S, PGRP-L, PGRP-Iα and PGRP-Iβ — each displaying a peptidoglycan-binding domain (also known as a PGRP domain) 27. Analysis of the tissue distribution of PGRP indicates a non-uniform expression: whereas PGRP-S is strongly expressed mostly in polymorphonuclear cells, PGRP-L expression is high in the liver, and PGRP-Iα and PGRP-Iβ seem to display a restricted expression in the esophagus 27. Consistent with the presence of a PGRP domain, it has been shown that each mammalian PGRP is able to bind peptidoglycan with high affinity 28, 29. In addition, only PGRP-L seems to display a lytic activity towards peptidoglycan; indeed, PGRP-L is an N-acetylmuramoyl-L-alanine amidase, which allows this enzyme to cleave peptidoglycan between the sugar moiety and the peptide moiety, in a similar fashion as Drosophila PGRP-SC1B 25, 30. With the recent discovery of the importance of innate immune detection of DAP-type vs. LYS-type peptidoglycan by Drosophila PGRP (see above) and Nods (see below), it will be of importance to analyze carefully the binding specificity of mammalian PGRP towards distinct peptidoglycan subtypes.

Among the four mammalian PGRP described, the function of PGRP-Iα and PGRP-Iβ remains unknown, and most research thus far has focused on PGRP-L and PGRP-S. The limited data on PGRP-L define this protein as a peptidoglycan lytic enzyme 25, 30, thus suggesting a role in the innate immune response towards peptidoglycan. However, further investigation is required to establish whether this protein does indeed exhibit a scavenger function as has been shown for the Drosophila homolog, PGRP-SC1B 24.

PGRP-S remains so far the most studied of the mammalian PGRP types. PGRP-S binds Gram-positive peptidoglycan with high affinity although whether it can bind to Gram-negative peptidoglycan remains controversial 24, 2729. Nevertheless, a bacteriostatic activity of PGRP-S has only been shown towards Gram-positive bacteria 28. More importantly, the analysis of the phenotype of PGRP-S-deficient mice has revealed a role of this protein in innate immunity to Gram-positive bacteria 31. PGRP-S-deficient mice are more susceptible than wild-type mice to intraperitoneal challenge with Bacillus subtilis; susceptibility to Gram-negative bacteria is unchanged 31. The reason behind this increased susceptibility in the PGRP-S-deficient mice resides in the impaired ability of neutrophils to kill certain Gram-positive organisms once the bacteria are intracellular 31. However, the mechanism involving PGRP-S in this process remains undefined.

4.3 Nod1 and Nod2

Nod1 and Nod2 are cytosolic proteins involved in innate immune defense, through pathways that are likely to be independent of TLR signaling 32, 33. Initial studies have demonstrated that Nod1 is an upstream activator of NF-κB 34, 35, and that the Nod1 pathway is triggered in the cytosol of epithelial cells infected with the Gram-negative entero-invasive bacteria, Shigella flexneri 36. In parallel with these studies, Nod2 has been identified as a close homolog of Nod1 but its expression is more pronounced in cells of the myeloid lineage 37. Importantly, Nod2 has also been identified as the first susceptibility gene involved in the etiology of Crohn's disease, an inflammatory bowel disease known to be influenced by both genetic and environmental factors 38, 39. Recent findings have allowed the characterization of the bacterial motifs detected within the cytosolic compartment by Nod1 and Nod2. In both cases, Nod1 and Nod2 detect distinct sub-structures that make up the peptidoglycan polymer 4043.

Nod2 is a general sensor for both Gram-positive and Gram-negative bacteria since biochemical and functional analysis has identified muramyl dipeptide (MDP) — the minimal motif in all peptidoglycans — as the essential structure recognized by Nod2 42, 43. Further analysis of the peptidoglycan structural requirements allowing sensing by Nod2 have shown that, in addition to MDP, Nod2 can detect Muramyl-TriLYS but not Muramyl-TriDAP44. Interestingly, the most common mutation in Nod2 associated with Crohn's disease — a frame-shift mutation resulting in the truncation of the terminal LRR — results in a protein product that no longer detects peptidoglycan 38, 45. Although the implications of these findings are still not fully understood, it appears that lack of bacterial sensing may contribute to the pathology of this disease, at least in some cases 45. A loss of surveillance activity by Nod2 may result in the inability of local responses in the intestinal mucosa to control bacterial infection thereby initiating systemic responses and leading to aberrant inflammation 46.

In contrast to Nod2, which should detect any peptidoglycan owing to its ability to sense MDP, Nod1 presents a strict sensing specificity towards DAP-type peptidoglycan 40, 41. Indeed, Nod1 detects a single muropeptide, GM-TriDAP, which is produced as a peptidoglycan degradation product in Gram-negative bacterial metabolism 41. Some Gram-positive bacteria, such as Listeria monocytogenes, Bacillus cereus and Bacillus anthracis, also contain DAP instead of LYS in their peptidoglycan; in the caseof B. subtilis, the DAP amino acid is modified through an amidation reaction, resulting in loss of peptidoglycan sensing through Nod1 44. However, although it is predicted that these specific Gram-positive peptidoglycans are detected by Nod1, evidence that Nod1 is actually involved in detection of any Gram-positive bacteria is still lacking. Investigation into the minimal peptidoglycan motif detected by Nod1 has revealed that, out of the GM-TriDAP muropeptide naturally produced by bacteria, the dipeptide moiety D-Glu-meso-DAP is sufficient to trigger Nod1 activation 40, 44.

As a next step towards understanding the precise contribution of Nod1 and Nod2 to innate immunity, several challenging issues remain to be investigated. (i) What is the functional interplay between TLR and Nods? (ii) How does peptidoglycan come in contact with Nod1 and Nod2 in the cytosol? (iii) Is there a link between Nods and PGRP in the host response to peptidoglycan? (iv) Do mice that are defective for either the Nod1 gene or the Nod2 gene display susceptibility to specific bacterial pathogens?

5 Conclusions

  1. Top of page
  2. Abstract
  3. 1 Introduction
  4. 2 Study of the role of peptidoglycan in innate immunity during the pre-Toll/TLR/ Nod era
  5. 3 Peptidoglycan triggers innate immune responses in Drosophila
  6. 4 Peptidoglycan detection in mammals
  7. 5 Conclusions

In both Drosophila and mammals, peptidoglycan plays a key role in triggering immune responses to bacteria. The recent discovery of PGRP and Nods has allowed us to revisit the immunomodulatory properties of this bacterial cell wall component. Research in the next few years will be aimed at placing the PGRP- and Nod-dependent pathways in the global scheme of innate immune responses to microbes; so far such research has been focused on TLR.

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