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Enemy attraction: bacterial agonists for leukocyte chemotaxis receptors

Nature Reviews Microbiology volume 13, pages 95–104 (2015)Cite this article

Subjects

Key Points

  • Recognition of invading bacteria is a crucial task for the human innate immune system to initiate the first line of defence against infections. For this purpose various receptors have evolved, each with different specificities for conserved microbial molecules. One important function of these receptors is to promote the migration of immune cells to the centre of infection along a gradient of microbial- or host-derived chemoattractants. This mechanism is called chemotaxis and is a crucial prerequisite for the elimination of pathogens.

  • Certain bacterial peptides can function as potent leukocyte attractants. Owing to the characteristics of bacterial translation, bacterial proteins are synthesized with a formylated methionine at the amino terminus. This feature is exploited by the human innate immune system because formylated peptides are identified as chemokines for leukocytes.

  • The chemoattractant receptor repertoire is limited and comprises members of the family of G protein-coupled receptors (GPCRs). Among them, the human formyl peptide receptor 1 (FPR1) is specialized to detect formylated peptides. Among the two orthologues of FPR1, only FPR2 has been confirmed to detect microbial peptides; FPR2 also detects endogenous ligands.

  • Recently, particular interest in FPR2 has arisen owing to the description of bacterial FPR2 ligands. These include the phenol-soluble modulin (PSM) peptides, which are cytotoxic at high concentrations and are secreted by Staphylococcus aureus and other staphylococci. FPR2 was further shown to respond differently to pathogenic and non-pathogenic staphylococcal strains according to the production of PSMs.

  • In addition to staphylococci, other bacteria such as Helicobacter pylori or enterococci activate FPR2. However, only in some instances has the nature of the agonists been identified.

  • Short-chain fatty acids are products of the energy metabolism of fermenting bacteria. They are recognized by the GPCRs GPR41 and GPR43 to mediate neutrophil chemotaxis and contribute to intestinal epithelial homeostasis.

  • Bacteria have evolved strategies to evade the host response by synthesizing molecules that block chemokine receptors. The recognition of bacterial chemotactic molecules may be beneficial for the host or, in some instances, also for pathogens taking advantage of inflammation. Moreover, chemotactic molecules are not only crucial for infection, they are also secreted by commensal bacteria and regulate epithelial homeostasis in the gut.

  • In conclusion, the field of research on microbial leukocyte chemoattractants offers interesting avenues for elucidating the complex interplay of pathogens and commensals with the immune system. Recognition of bacterial infection by the host innate immune system leads to chemotactic leukocyte influx.

Abstract

The innate immune system recognizes conserved microorganism-associated molecular patterns (MAMPs), some of which are sensed by G protein-coupled receptors (GPCRs), and this leads to chemotactic leukocyte influx. Recent studies have indicated that these processes are crucial for host defence and rely on a larger set of chemotactic MAMPs and corresponding GPCRs than was previously thought. Agonists, such as bacterial formyl peptides, enterococcal pheromone peptides, staphylococcal peptide toxins, bacterial fermentation products and the Helicobacter pylori peptide HP(2–20), stimulate specific GPCRs. The importance of leukocyte chemotaxis in host defence is highlighted by the fact that some bacterial pathogens produce chemotaxis inhibitors. How the various chemoattractants, receptors and antagonists shape antibacterial host defence represents an important topic for future research.

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Figure 1: Recruitment of polymorphonuclear neutrophils from the bloodstream.
Figure 2: Induction of leukocyte chemotaxis.
Figure 3: Activation of GPCRs on neutrophils.

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Acknowledgements

The authors are grateful for helpful discussions with their collaborators and colleagues. The authors' research is funded by the German Research Council grants SFB685 and PE805/5-1 to A.P. and TRR34 to A.P. and D.K., and by the Fortüne programme of the Medical Faculty Tübingen to D.K..

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  1. Cellular and Molecular Microbiology Division, Interfaculty Institute of Microbiology and Infection Medicine, University of Tübingen, Tübingen, 72076, Germany

    Dominik Alexander Bloes, Dorothee Kretschmer & Andreas Peschel

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  1. Dominik Alexander Bloes
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HeliQuest

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Glossary

Complement

An innate immune defence system of > 25 proteins that recognizes foreign objects and targets them for destruction or phagocytosis.

Leukotrienes

A class of eicosanoids that are derived from arachidonic acid and have pro-inflammatory activities.

Phenol-soluble modulins

(PSMs). Staphylococcal secreted peptides with a length of 20–44 amino acids that are potent bacterial agonists for formyl peptide receptor 2 (at nanomolar concentrations) and cytolytic toxins (at micromolar concentrations).

Vomeronasal sensory neurons

An olfactory sensory sytem that detects chemical stimuli such as pheromones, which are produced during mating by many animals.

Hydrophobic moment

A measure of the amphiphilicity of a protein helix.

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Bloes, D., Kretschmer, D. & Peschel, A. Enemy attraction: bacterial agonists for leukocyte chemotaxis receptors. Nat Rev Microbiol 13, 95–104 (2015). https://doi.org/10.1038/nrmicro3390

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