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Review
. 2011 Dec 12;10(2):112-22.
doi: 10.1038/nrmicro2711.

Candida albicans morphogenesis and host defence: discriminating invasion from colonization

Neil A R Gow  1 , Frank L van de Veerdonk, Alistair J P Brown, Mihai G Netea
Affiliations
Review

Candida albicans morphogenesis and host defence: discriminating invasion from colonization

Neil A R Gow et al. Nat Rev Microbiol. .

Abstract

Candida albicans is a common fungal pathogen of humans that colonizes the skin and mucosal surfaces of most healthy individuals. Until recently, little was known about the mechanisms by which mucosal antifungal defences tolerate colonizing C. albicans but react strongly when hyphae of the same microorganism attempt to invade tissue. In this Review, we describe the properties of yeast cells and hyphae that are relevant to their interaction with the host, and the immunological mechanisms that differentially recognize colonizing versus invading C. albicans.

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Figures

Figure 1
Figure 1. Candida albicans tissue invasion
The figure shows several steps in tissue invasion by C. albicans of a stylised epithelial cell surface: adhesion to the epithelium; epithelial penetration and invasion by hyphae; vascular dissemination, which involves hyphal penetration and seeding of yeast cells into the bloodstream; and finally endothelial colonization and penetration during disseminated disease.
Figure 2
Figure 2. Structure of the Candida albicans cell wall
Two layers can be distinguished in the C. albicans cell wall. The outer layer is highly enriched with O- and N-linked glycoproteins whereas the inner layer contains the skeletal polysaccharides chitin and β-1,3 glucan that confer strength and cell shape. The outer cell wall proteins are attached to this framework predominantly by glycosylphosphatidylinositol (GPI)-remnants that are linked to the skeleton through a more flexible β-1,6 glucan.
Figure 3
Figure 3. Different stimuli promote the formation of subtly different Candida albicans hyphae
(A) A variety of environmental triggers modulate hypha formation through the cyclic AMP (cAMP)–protein kinase A (PKA) signalling pathway. Muramyl dipeptide and CO2 act directly on the adenylate cyclase Cyr1 and other signals, including amino acids and glucose, act on Cyr1 indirectly. Many signals act through the transcription factor Efg1 to activate the hypha-specific cyclin Hgc1. The cyclins Ccn1 and Hgc1 form complexes with the cyclin-dependent kinase (CDK) Cdc28. These complexes promote persistent actin polarization for hyphal growth. Farnesol is a quorum-sensing molecule that accumulates at high C. albicans cell densities and inhibits hyphal formation. Low temperatures inhibit hyphal formation through the inhibitory activity of the molecular chaperone heat shock protein 90 (Hsp90) on the PKA signalling pathway, which involves Ras1. The environmental triggers that induce signalling through the Ccn1 pathway are thought to be similar to those that induce signalling through the PKA pathway but the precise details of Ccn1 activation are unclear. (B) Additional environmental factors stimulate hypha formation through alternative signalling pathways. These factors include ambient pH (through the Rim101 pathway), physical embedding of C. albicans cells within a matrix (through the transcription factor Czf1), hypoxia (which involves the transcription factors Efg1 and Efh1) and low nitrogen due to starvation (which activates hyphal development by the transcription factor Cph1). (C) In addition, genotoxic stress by hydrogen peroxide (H2O2), UV radiation, hydroxyurea or gene deletions leading to DNA damage or interference with DNA replication cell-cycle checkpoints also cause cell filamentation. The alternative signalling mechanisms illustrated in parts A, B and C will yield different signalling outputs, and as a result the cell surface and immunological properties of these hyphal forms are likely to differ (denoted by the different colours of hyphae).
Figure 4
Figure 4. The main pattern recognition receptors involved in recognizing Candida albicans
The soluble lectin receptor mannose-binding lectin (MBL) can bind mannose-rich structures. In addition, the membrane-bound C-type lectin receptors macrophage mannose receptor (MMR), dendritic cell-specific ICAM3-grabbing non-integrin (DC-SIGN) and the macrophage-inducible C-type lectin (Mincle) also recognize mannose-rich structures. Dectin-1 can bind β-glucans and dectin-2, together with the Fc gamma receptor (FcγR), recognizes α-mannans. TLR4 recognizes O-linked mannans and TLR2 can recognize phospholipomannans or, together with galectin-3, recognizes β-mannosides. TLR9 is located in the cytosol and recognises fungal DNA. Furthermore, the NOD-like receptor NLRP3 forms an inflammasome complex with apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) and the enzyme caspase-1. The ligand that triggers the Nlrp3 inflammasome is currently unknown.
Figure 5
Figure 5. Colonization versus invasion
(A) Candida albicans colonization of the skin and mucosal surfaces. In healthy individuals, mucosal surfaces are often colonized with C. albicans. The relatively small numbers of C. albicans do not induce epithelial cell damage, and as a result no cytokine response is induced from the epithelial cells or mucosal macrophages and dendritic cells. In C. albicans yeast cells, the pathogen-associated molecular patterns (PAMPs) responsible for inflammasome activation are hidden, and no interleukin (IL)-1β or T helper 17 (TH17) responses are induced. C. albicans yeast cells can trigger a mitogen-activated protein kinase (MAPK) pathway leading to the activation of the transcription factors c-Jun and c-Fos, but this is not sufficient to trigger a cytokine response in epithelial cells. The normal microbial flora acts as a natural antagonist against abundant fungal growth. (B) Invasion of mucosal surfaces by C. albicans . The switch between yeast and hyphae has an important role in the invasiveness of C. albicans. On one hand, the hyphae induce cytokine production from epithelial cells by inducing not only the MAPK pathway described in (A) but also a second MAPK pathway that leads to the activation of MKP1. This triggers the production of IL-1α and IL6. On the other hand, hyphae activate the inflammasome and induce IL-1β production in immune cells such as macrophages, and stimulate TH17 cells to produce cytokines. TH17-produced cytokines such as IL-17 activate neutrophils, while IL-22 induces the release of defensins from epithelial cells, both crucial components of mucosal antifungal defense. Products of tryptophan metabolism released by C. albicans hyphae can downmodulate TH17 responses .
Figure 5
Figure 5. Colonization versus invasion
(A) Candida albicans colonization of the skin and mucosal surfaces. In healthy individuals, mucosal surfaces are often colonized with C. albicans. The relatively small numbers of C. albicans do not induce epithelial cell damage, and as a result no cytokine response is induced from the epithelial cells or mucosal macrophages and dendritic cells. In C. albicans yeast cells, the pathogen-associated molecular patterns (PAMPs) responsible for inflammasome activation are hidden, and no interleukin (IL)-1β or T helper 17 (TH17) responses are induced. C. albicans yeast cells can trigger a mitogen-activated protein kinase (MAPK) pathway leading to the activation of the transcription factors c-Jun and c-Fos, but this is not sufficient to trigger a cytokine response in epithelial cells. The normal microbial flora acts as a natural antagonist against abundant fungal growth. (B) Invasion of mucosal surfaces by C. albicans . The switch between yeast and hyphae has an important role in the invasiveness of C. albicans. On one hand, the hyphae induce cytokine production from epithelial cells by inducing not only the MAPK pathway described in (A) but also a second MAPK pathway that leads to the activation of MKP1. This triggers the production of IL-1α and IL6. On the other hand, hyphae activate the inflammasome and induce IL-1β production in immune cells such as macrophages, and stimulate TH17 cells to produce cytokines. TH17-produced cytokines such as IL-17 activate neutrophils, while IL-22 induces the release of defensins from epithelial cells, both crucial components of mucosal antifungal defense. Products of tryptophan metabolism released by C. albicans hyphae can downmodulate TH17 responses .
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