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  • Review Article
  • Published:

Peptidoglycan recognition proteins: modulators of the microbiome and inflammation

Nature Reviews Immunology volume 11, pages 837–851 (2011)Cite this article

Subjects

Key Points

  • All multicellular eukaryotes live in symbiotic associations with microorganisms, and the immune system accommodates host colonization by symbiotic microorganisms, maintains microbiota–host homeostasis and defends against pathogens.

  • One family of antibacterial pattern recognition molecules — the peptidoglycan recognition proteins (PGRPs) — has evolved a variety of mechanisms to control host interactions with mutualistic, commensal and parasitic microorganisms to benefit both invertebrate and vertebrate hosts.

  • PGRPs are antibacterial proteins of the innate immune system that are conserved from insects to mammals. In invertebrates, PGRPs function as soluble or cell-surface pattern recognition receptors and hydrolyse peptidoglycan, whereas in vertebrates they also directly kill bacteria.

  • In Drosophila melanogaster, PGRPs are upstream pattern recognition molecules that activate the IMD and Toll pathways and induce the production of antimicrobial peptides, which control intestinal bacteria and defend against infections. PGRPs also control the level of pro-inflammatory peptidoglycan through their amidase activity.

  • In mosquitoes, PGRPs not only defend the insect against bacterial infections, but also regulate symbiotic bacteria, as well as the host response to malaria parasites. In tsetse flies, PGRPs control endosymbiotic bacteria and trypanosome parasites.

  • In squid, PGRPs control the winnowing and establishment of symbiotic luminescent bacteria in the squid light organ. In zebrafish, PGRPs protect the embryos from infections and enable their survival.

  • In mammals, PGRPs control the acquisition and maintenance of normal gut microorganisms, which protect the host from enhanced inflammation, tissue damage and colitis.

Abstract

All animals, including humans, live in symbiotic association with microorganisms. The immune system accommodates host colonization by the microbiota, maintains microbiota–host homeostasis and defends against pathogens. This Review analyses how one family of antibacterial pattern recognition molecules — the peptidoglycan recognition proteins — has evolved a fascinating variety of mechanisms to control host interactions with mutualistic, commensal and parasitic microorganisms to benefit both invertebrate and vertebrate hosts.

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Figure 1: The structure of PGRPs.
Figure 2: Insect PGRPs recognize peptidoglycan and regulate multiple defence pathways.
Figure 3: Drosophila melanogaster PGRPs protect the gut from infections and maintain gut microbiome homeostasis.
Figure 4: In blood-sucking insects, PGRPs maintain the balance between symbiotic bacteria and protozoal parasites.
Figure 5: Euprymna scolopes PGRPs control colonization and maintenance of the luminescent bacterium Vibrio fischeri within the light organ of the squid.
Figure 6: Vertebrate PGRPs are bactericidal, defend against infections, regulate intestinal microorganisms and protect mammals against colitis.

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Acknowledgements

Research in the authors' laboratories is supported by the National Institutes of Health (D.G. and R.D.) and the Action Concertée Insitative, Fondation pour la Recherche Médicale, Institut Universitaire de France, and Agence Nationale de la Recherche (J.R.).

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  1. Institut de Biologie du Développement de Marseille-Luminy, UMR6216 CNRS et Aix-Marseille Universites, Parc Scientifique de Luminy, Marseille, France

    Julien Royet

  2. Indiana University School of Medicine – Northwest, Gary, 46408, Indiana, USA

    Dipika Gupta & Roman Dziarski

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  1. Julien Royet
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Correspondence to Julien Royet or Roman Dziarski.

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Glossary

Eukaryotes

Organisms (such as animals, plants and fungi) whose cells contain genetic material contained within a membrane-enclosed nucleus.

Symbiotic

Symbiosis is a physical association between two organisms and includes mutualism, commensalism and parasitism. In common (non-scientific) usage it is often assumed to be beneficial to both organisms.

Mutualistic

A form of symbiosis that is beneficial to both organisms involved.

Commensal

A form of symbiosis in which one organism benefits and the other derives neither benefit nor harm.

Microbiome

The microbiome is the entire community of microorganisms that live in or on the body of a multicellular eukaryotic organism. Because in many cases these microorganisms can only be characterized by genetic methods, the term microbiome is often used to refer to the collective genomes present in all microorganisms in a given microbial community.

Prokaryotes

Simple organisms (such as bacteria) whose cells lack a membrane-enclosed nucleus and membrane-enclosed organelles.

Pattern recognition molecules

Proteins that recognize molecular patterns that are characteristic of microbial molecules but not present in the host, such as peptidoglycan (which is found in the cell walls of all bacteria) or lipopolysaccharide (which is found in the cell walls of Gram-negative bacteria). Some pattern recognition molecules are found on the surface of host cells and function as pattern recognition receptors to activate host cells, whereas others are secreted and function to trigger pro-inflammatory cascades or help to remove microorganisms.

Parasitic

A form of symbiosis that is beneficial to one organism and detrimental to the other.

Prophenoloxidase cascade

A cascade of enzymatic reactions that generates quinones, which are toxic to microorganisms, and melanin pigments, which restrict the spreading of microorganisms within the host. It is an important component of the innate immune response in invertebrates.

Toll pathway

A signalling cascade in insects that regulates the expression of antimicrobial peptides after infection by fungi or Gram-positive bacteria. Detection of fungi by GNBP3 and of bacteria by circulating peptidoglycan recognition proteins (PGRPs) triggers the cleavage of the cytokine Spätzle, which then activates the Toll receptor, and this initiates the activation of the NF-κB-like transcription factors Dif and Dorsal and their translocation into the nucleus. This pathway also controls dorsoventral patterning during embryogenesis.

Antimicrobial peptides

(AMPs). Polypeptides that are typically less than 100 amino acids and that have an important role in innate immune responses by providing broad-spectrum antimicrobial activity against pathogenic microorganisms. There are different types of AMP that promote microbial killing by various mechanisms, but many function by disrupting the membranes of microorganisms.

IMD pathway

A signalling cascade in insects (named after 'immunodeficiency' mutant flies) that corresponds closely to the mammalian tumour necrosis factor receptor signalling pathway. This cascade is mainly activated by Gram-negative bacteria, which are recognized by the upstream receptors PGRP-LC and PGRP-LE. Intracellular signalling involves the death domain-containing protein IMD, IκB kinase, FADD, Dredd, TAK1 and the NF-κB-like protein Relish. In contrast to the Toll pathway, the IMD pathway has no known role in development.

Autophagy

Autophagocytosis that involves the degradation of the cell's own components through the lysosomal machinery. This process has a role in normal cell growth and development, and also has a protective role against infection with intracellular pathogens.

Reactive oxygen species

(ROS). Aerobic organisms derive their energy from the reduction of oxygen. The metabolism of oxygen, and in particular its reduction through the mitochondrial electron-transfer chain, generates by-products such as superoxide (O2−), hydrogen peroxide (H2O2) and hydroxyl radicals (•OH). These three species and the unstable intermediates that are formed by lipid peroxidation are known as ROS. ROS can damage important intracellular targets such as DNA, carbohydrates and proteins.

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Royet, J., Gupta, D. & Dziarski, R. Peptidoglycan recognition proteins: modulators of the microbiome and inflammation. Nat Rev Immunol 11, 837–851 (2011). https://doi.org/10.1038/nri3089

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