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  • Review Article
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An integrated model of the recognition of Candida albicans by the innate immune system

Key Points

  • Recognition of fungi by the innate immune system depends on 'tasting' several pathogen-associated molecular patterns (PAMPs) in the fungal cell wall. Specific receptor systems have evolved for the recognition of the major polysaccharide cell wall components, such as the mannose receptor (MR) and DC-SIGN for recognition of branched N-linked mannan, Toll-like receptor 4 (TLR4) for linear O-linked mannan, galectin 3 for β-mannosides, complement receptor 3 (CR3) for β-(1,6)-glucan, and dectin 1 and TLR2 for β-glucan and phospholipomannan.

  • Despite overlapping and sometimes redundant functions, each ligand–receptor system activates specific intracellular pathways, and this has distinct consequences for the activation of the various arms of the immune response.

  • Differential expression of the various pattern-recognition receptors (PRRs) is an important mechanism for the cell-type-specific response to fungal pathogens.

  • The fully integrated response to a specific pathogen depends on the mosaic of PRRs and receptor complexes that is engaged.

  • The recognition pathways might operate singly or, more likely, in combination. Co-stimulation via multiple PAMP–PRR combinations might increase both the sensitivity and the specificity of the immune recognition process.

  • Although described here for Candida albicans, these principles of innate immune recognition can be considered as a blueprint for pattern recognition of all pathogenic microorganisms by the innate immune response.

Abstract

The innate immune response was once considered to be a limited set of responses that aimed to contain an infection by primitive 'ingest and kill' mechanisms, giving the host time to mount a specific humoral and cellular immune response. In the mid-1990s, however, the discovery of Toll-like receptors heralded a revolution in our understanding of how microorganisms are recognized by the innate immune system, and how this system is activated. Several major classes of pathogen-recognition receptors have now been described, each with specific abilities to recognize conserved bacterial structures. The challenge ahead is to understand the level of complexity that underlies the response that is triggered by pathogen recognition. In this Review, we use the fungal pathogen Candida albicans as a model for the complex interaction that exists between the host pattern-recognition systems and invading microbial pathogens.

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Figure 1: The structure of the Candida albicans cell wall.
Figure 2: Cell populations and pattern-recognition receptors involved in Candida albicans recognition.
Figure 3: Recognition of Candida albicans at the membrane level.
Figure 4: Candida albicans mechanisms to escape the innate response using pattern-recognition receptors.

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Acknowledgements

This work was supported by a Vidi Grant from Netherlands Organization for Scientific Research to M.G.N., and by the Wellcome Trust to N.A.R.G. and G.D.B.

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Correspondence to Mihai G. Netea or Neil A. R. Gow.

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DATABASES

Entrez Genome project

Borrelia burgdorferi

Candida albicans

Saccharomyces cerevisiae

Schistosoma mansoni

Glossary

Innate immune system

The suite of host responses to microbial invaders that results in rapid defence without requiring prior stimulation.

Dendritic cells

'Professional' antigen-presenting cells that are found in the T-cell areas of lymphoid tissues and as minor cellular components in most tissues. They have a branched or dendritic morphology and are important stimulators of T-cell responses.

Cytokines

Biologically active molecules that are released by cells and that affect the function of other cells.

Fcγ receptor

A surface molecule on various cells that binds to the Fc regions of immunoglobulins, thereby initiating effector functions.

T helper 1

An immune response that is characterized by a subset of helper T-cells that secrete a particular set of cytokines, including interleukin 2, interferon-γ and TNFα, the main function of which is to stimulate phagocytosis-mediated defences against intracellular pathogens.

C-type lectin

C-type lectins are largely calcium-dependent animal lectins that are carbohydrate-binding proteins. The binding activity of C-type lectins is based on the structure of the carbohydrate-recognition domain, which is highly conserved in this family.

Chemokines

Small, inducibly secreted proteins that induce the activation and migration of lymphocytes.

Complement

A part of the innate immune system that comprises serum proteins that can protect against infection.

Type I interferons

Interferons that are rapidly induced by virus replication, as well as by some bacterial and fungal infections.

TH2

A type of activated T helper cell that participates in phagocytosis-independent responses and that downregulates pro-inflammatory responses that are induced by TH1 cells. TH2 cells secrete interleukin 4 (IL-4), IL-5, IL-6 and IL-10.

Regulatory T-cell

A small population of CD4+ T-cells that expresses the transcription factor forkhead box P3 and that has suppressor activity towards other T-cells either by cell–cell contact or cytokine release.

Zymosan

Particulate preparation of S. cerevisiae cell walls that is rich in β-glucans and mannan and that can be used to activate the innate immune system.

Tetraspanin

A family of transmembrane proteins that have four transmembrane domains and two extracellular domains of different sizes. The function of tetraspanins is unclear, but they seem to interact with many other transmembrane proteins and form large multimeric protein networks.

TH17 response

The TH17 subpopulation are T-cells that release mainly IL-17, which has both neutrophil chemotactic activity and the potential to promote autoimmunity.

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Netea, M., Brown, G., Kullberg, B. et al. An integrated model of the recognition of Candida albicans by the innate immune system. Nat Rev Microbiol 6, 67–78 (2008). https://doi.org/10.1038/nrmicro1815

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