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Peptidoglycan recognition by the innate immune system

  • Review Article
  • Published:

From Nature Reviews Immunology

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Key Points

  • Peptidoglycan in bacterial cell walls is sensed by multiple pattern-recognition receptors, including nucleotide-binding oligomerization domain-containing protein 1 (NOD1), NOD2, NOD-, LRR- and pyrin domain-containing 3 (NLRP3) and peptidoglycan recognition protein 1 (PGLYRP1), that trigger inflammatory responses in immune and nonimmune cells throughout the body.

  • As an important structural component of bacterial cell walls, the sensitivity to degradation of peptidoglycan plays a vital role in determining the overall inflammatory response during infection. Peptidoglycan degradation is regulated by bacterial cell wall modifications that vary substantially among bacterial species and can be altered by exposure to antibiotics.

  • Peptidoglycan fragments are detected throughout the body in the absence of obvious infection. Some circulating peptidoglycan fragments can be traced to the gut microbiota.

  • These circulating peptidoglycan fragments are necessary for proper immune cell development and homeostasis. For example, circulating peptidoglycan fragments induce NOD1 signalling in phagocytes, altering their maturation and antimicrobial function.

  • Circulating peptidoglycan fragments have been shown to affect neuronal cell development in the brain and in the developing fetus.

Abstract

The innate immune system recognizes microbial products using germline-encoded receptors that initiate inflammatory responses to infection. The bacterial cell wall component peptidoglycan is a prime example of a conserved pathogen-associated molecular pattern (PAMP) for which the innate immune system has evolved sensing mechanisms. Peptidoglycan is a direct target for innate immune receptors and also regulates the accessibility of other PAMPs to additional innate immune receptors. Subtle structural modifications to peptidoglycan can influence the ability of the innate immune system to detect bacteria and can allow bacteria to evade or alter host defences. This Review focuses on the mechanisms of peptidoglycan recognition that are used by mammalian cells and discusses new insights into the role of peptidoglycan recognition in inflammation, metabolism, immune homeostasis and disease.

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Figure 1: Structure of peptidoglycan highlighting enzymatic degradation, innate ligands and modification points.
Figure 2: Innate immune sensing signalling pathways.
Figure 3: Intestinal and systemic impact of peptidoglycan derived from gut microbiota.

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Authors and Affiliations

  1. Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center,

    Andrea J. Wolf & David M. Underhill

  2. Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, 90048, California, USA

    David M. Underhill

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  1. Andrea J. Wolf
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  2. David M. Underhill
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Both authors contributed to the writing of this Review.

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Correspondence to Andrea J. Wolf or David M. Underhill.

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Glossary

Pattern-recognition receptors

(PRRs). Innate immune receptors expressed at the cell surface and in the cytoplasm that sense small molecules that are common to several different microorganisms.

Lipoproteins

Molecules embedded in the cell wall of both Gram-positive and Gram-negative bacteria that play diverse functional roles, including adhesion, signalling and nutrient uptake and that activate signalling through Toll-like receptor 2 (TLR2) in combination with either TLR1 or TLR6.

Staphylococcus aureus

A Gram-positive bacterium that behaves as an important commensal bacteria and opportunistic pathogen.

Lipopolysaccharide

(LPS). A component of the cell wall of most Gram-negative bacteria and the innate immune ligand for the membrane receptor Toll-like receptor 4 (TLR4).

Lipoteichoic acids

(LTAs). LTAs and teichoic acids are hydrophilic polyphosphate polymers anchored by a glycolipid link to the bacterial membrane or covalently bound to the cell wall peptidoglycan, respectively. They are specific to Gram-positive bacteria and have been reported to activate Toll-like receptor 2 (TLR2).

Bacillus anthracis

Anthrax. A Gram-positive, spore-forming bacterium that is a common livestock pathogen and an occasional human pathogen.

Lysostaphin

A zinc-dependent endopeptidase with bacteriolysin activity that is produced by certain Staphylococci strains. It specifically cleaves the pentaglycine bridge found only in peptidoglycan generated by Staphylococcus aureus and a few other Staphylococci strains.

Mutanolysin

An N-acetylmuramidase that cleaves the β(1–4)-linkage between N-acetylmuramic acid and N-acetylglucosamine in the sugar backbone of peptidoglycan. Mutanolysin treatment of several strains of Gram-positive bacteria results in bacterial lysis.

PAM3CSK4

A small synthetic triacylated lipopeptide ligand for TLR2–TLR1 heterodimers of Toll-like receptors. It functions as a mimic of the acylated amino terminus of lipoproteins found in the cell wall of both Gram-positive and Gram-negative bacteria that activate TLR2–TLR1.

NOD-like receptors

(NLRs). A large family of related proteins that function as cytosolic innate immune sensors and share a general three domain structure. All NLRs contain a nucleotide- binding and oligomerization domain (NACHT). Most have a C-terminal leucine-rich repeat domain, and the N-terminus is composed of various combinations of effector domains that can include the caspase recruitment domain (CARD), PYRIN domains, baculoviral inhibitor of apoptosis repeat domains or the transactivator domain.

Tracheal cytotoxin

(TCT). A small fragment of peptidoglycan from the Gram-negative bacteria Bordetella pertussis and Neisseria gonorrhoeae composed of a disaccharide and a diaminopimelic acid (DAP)-containing tetrapeptide that is recognized by nucleotide-binding oligomerization domain-containing protein 1 (NOD1).

Thapsigargin

An inhibitor of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) channels in the membrane of the endoplasmic reticulum (ER) responsible for transporting Ca2+ from the cytoplasm into the ER. Thapsigargin treatment results in an elevation in cytosolic Ca2+ while depleting ER Ca2+ stores, leading to ER stress and activation of Ca2+-dependent cell signalling pathways.

Inflammasome

A large multiprotein complex that contains certain NOD-like receptors, retinoic acid RIG-I-like receptors and IFI200 proteins, the adaptor protein ASC and pro-caspase 1. Assembly of the inflammasome leads to the activation of caspase 1, which cleaves pro-interleukin-Iβ (pro-IL-1β) and pro-IL-18 to generate the active forms of these pro-inflammatory cytokines.

Lysozyme

Also known as muramidase. A small antibacterial enzyme produced by innate immune phagocytes. A glycoside hydrolase that cleaves the β(1–4) linkage between N-acetylmuramic acid (MurNAc) and N-acetylglucosamine (NAG) in bacterial peptidoglycan.

β-Lactam antibiotics

β-Lactam antibiotics inhibit bacterial cell wall peptidoglycan synthesis, leading to a build-up of peptidoglycan intermediates and induction of bacterial autolysis. This class of broad spectrum antibiotics includes penicillins, cephalosporins, monobactams and carbapenems.

Hexokinase

The enzyme responsible for phosphorylating glucose, which is the first step in glycolysis.

Warburg effect

Describes the metabolic state of a cell that primarily produces ATP by elevating its rate of glycolysis even in the presence of sufficient levels of oxygen, which could be used to produce ATP by mitochondrial respiration. This is known as aerobic glycolysis and is a common feature of many cancer cells.

Paneth cells

Specialized epithelial cells found in the crypts of the small intestine epithelium that are responsible for producing large amounts of antimicrobial peptides (for example, α-defensins) and antimicrobial enzymes (for example, lysozyme) that help keep the gut microbiome in check and protect the epithelium from pathogenic bacteria.

Cryptopatches

Small aggregates of lymphocytes in the lamina propria of the small intestine thought to be the site of extrathymic T cell development; they contain lymphoid tissue inducer cells (LTis) and Group 3 innate lymphoid cells (ILC3s).

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Wolf, A., Underhill, D. Peptidoglycan recognition by the innate immune system. Nat Rev Immunol 18, 243–254 (2018). https://doi.org/10.1038/nri.2017.136

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