C albicans and the Host Immune System

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When C. albicans infects a host it enters into a battle with the host immune system, particularly cells of the innate immune system. Neutrophils and macrophages are involved in mopping up fungal cells found in the bloodstream, and it is important to know how both host and fungus respond during these interactions. The adaptive immune response is involved in determining the outcome of systemic infection, so interactions of C. albicans with the major antigen processing and presenting cells, dendritic cells, are also important. One of the major areas of recent improved understanding is the identification of host receptors and their corresponding fungal ligands. C. albi-cans-host cell receptor interactions have been recently reviewed by Filler (2006).

Dendritic cells stimulate C. albicans-specific lymphocyte proliferation, with recognition of C. albicans occurring mainly via the mannose receptor (Newman & Holly, 2001). The glycosylated portion of C. albicans mannoprotein 65 (MP65) was demonstrated to stimulate production of TNF-a and IL-6 by dendritic cells via the mannose receptor, while the protein portion of the same protein was found to stimulate dendritic cell maturation and T cell activation via toll-like receptors (TLRs) and the MyD88-dependent signalling pathway (Pietrella et al., 2006).

An elegant study by Romani et al. (2004) demonstrated that different macrophage surface receptors were involved in phagocytosis of unopsonised yeast and hyphal cells (Romani et al., 2004). Blocking the mannose receptor had the greatest effect on phagocytosis of yeast cells; with CR3 and dectin-1 also having significant effects. However, the mannose receptor had no effect on phagocytosis of hyphae, which was mediated mostly by CR3, dectin-1, and the FcyRII/III receptors. Binding of the mannose receptor was associated with a Type I cytokine responses, whereas entry via the FcyR receptors produced a Type II response (Romani et al., 2004). The mannose receptor, however, does not appear to be essential for host defence or phagocytosis in an intraperitoneal (i.p.) infection model of candidiasis (Lee et al., 2003).

The MyD88-dependent signalling pathway is essential for resistance to C. albi cans infection (Bellocchio et al., 2004; Villamon et al., 2004a). MyD88-deficient mice infected with C. albicans had significantly reduced survival and higher organ burdens compared to control mice (Villamon et al., 2004a). This was associated with reduced neutrophil infiltrates in vivo, and reduced proinflammatory cytokines in vitro. Innate and adaptive immune responses against C. albicans requires coordinated action of members of the TLR super family, which signal via the MyD88 adaptor (Bellocchio et al., 2004; Villamon et al., 2004a).

TLRs have been recently reviewed (Gil & Gozalbo, 2006). Macrophages deficient in either TLR2 or TLR4 demonstrated that TLR2, but not TLR4, is involved in anti-candidal defence (Blasi et al., 2005). TRL2-deficient mice were also shown to be more susceptible to C. albicans infections (Villamon et al., 2004c), with macrophages producing less TNF-a and macrophage inhibitory protein 2 (MIP2). However, a second study demonstrated that TLR2-deficent mice were more resistant to systemic disease (Netea et al., 2004). Differences found between the two studies may be due to different mouse strain backgrounds, or may reflect differences in the C. albicans strains used to infect the mice. Little research has examined differences in virulence between strains of C. albicans. C. albicans is thought to induce immunosuppression of mice via TLR2 and MyD88-mediated signals, which increase IL10 and survival of T regulatory cells (Tregs) (Netea et al., 2004; Sutmuller et al., 2006). However, TLR2 has been shown to be dispensable for cell-mediated immune responses (Villamon et al., 2004b).

TLR4-deficient mice showed no significant difference in survival and no differences were found in neutrophil recruitment for i.p. infection or macrophage TNF-a production, suggesting that TLR4 was dispensable for murine immune responses to C. albicans (Murciano et al., 2006). Different morphological forms of C. albicans are found to signal via either TLR2 or TLR4 (Blasi et al., 2005). Interaction of hyphal cells with peripheral blood mononuclear cells (PBMCs) or murine splenic lymphocytes stimulated IL 10 production in a TLR2-dependent manner (Blasi et al., 2005), while yeast cells induced IFN-y in a TLR4-dependent mechanism (Blasi et al., 2005), with the switch from yeast to hyphae losing the TLR4-mediated signal. C. albicans mannosylation mutants suggest that TLR4 recognises 0-linked mannoses on the cell surface, TLR2 is involved in recognition of ß-glucan and the mannose receptor recognises mannosyl groups (Table 5.3) (Netea et al., 2006). This suggests that yeast and hyphae display very different epitopes on their cell surfaces. Differential signalling through the TLRs produces differing immune responses, with TLR4 signalling producing proinflammatory cytokines, and TLR2 signalling producing anti-inflammatory cytokines (van der Graaf et al., 2005).

Dectin-1 is a receptor shown to bind ß-glucan (Table 5.3) and is important for macrophage phagocytosis (Lee et al., 2003; Gantner et al., 2005; Heinsbroek et al., 2005). ß-glucan is a key molecular pattern recognised by human polymorphonu-clear leukocytes (PMNs) (Lavigne et al., 2006). In differing studies dectin-1 deficient mice either showed no difference in their susceptibility to C. albicans infections

Table 5.3 Receptor-ligand interactions between host cells and C. albicans

Host receptor

C. albicans ligand



O-linked mannoses

Netea et al. (2006)



Netea et al. (2006)



Lee et al. (2003), Gantner

et al. (2005)


High mannose

McGreal et al. (2006)

structures (man9)



Kohatsu et al. (2006)

Mannose receptor

Mannosyl groups

Netea et al. (2006)

(Saijo et al., doi:10.1038/ni1425), or were more susceptible, with reduced lymphocyte infiltration and higher organ burdens (Taylor et al., 2006). Again, these differences may reflect different mouse strain backgrounds or C. albicans strains.

ß-glucan is largely protected in yeast cells, but is exposed during cell separation and then induces antimicrobial responses via dectin-1 (Gantner et al., 2005). Hyphal cells, which do not expose their ß-glucan, do not stimulate dectin-1 mediated responses (Gantner et al., 2005; Wheeler & Fink, 2006). Card9 has recently been identified as one of the key transducers of dectin-1 signalling, controlling dectin-1 mediated myeloid activation, cytokine production and innate antifungal activity (Gross et al., 2006). A mutant screen recently identified a number of genes involved in ß-glucan masking (Wheeler & Fink, 2006). Genes identified included those encoding proteins involved in protein mannosylation (MNN10, MNN11, OCH1, OST3, and OST4) and several transcription factors (ASF1, IES6, NOT4, and SSN8) (Wheeler & Fink, 2006). Disruption of several of these genes has been demonstrated to affect host immune responses and/or virulence (The Candida Genome Database).

C. albicans can also bind other receptors; including dectin-2, galectin-3, and DC-SIGN (Table 5.3). Dectin-2 recognises high mannose structures (McGreal et al., 2006) and, like dectin-1, preferentially binds hyphal cells (Sato et al., 2006). Binding of dectin-2 leads to phosphorylation of FcyRs, which mediate the signal from dectin-2, inducing innate immune responses (Sato et al., 2006). Galectin-3, expressed on epithelial cells, macrophages, and dendritic cells, binds to ß-1,2-oli-gomannosides (Kohatsu et al., 2006). Binding to galectin-3 directly induces death of C. albicans (Kohatsu et al., 2006). Although a synthetic analogue of ß-1,2-oli-gomannosides prevented colonisation of mouse gut epithelium (Dromer et al., 2002), galectin-3 was not required for recognition and endocytosis by endothelial cells, which is TLR2-mediated (Jouault et al., 2006). DC-SIGN (CD209) on human monocyte-derived dendritic cells is able to bind C. albicans, and in immature dendritic cells internalises the yeasts in specific DC-SIGN-enriched vesicles (Cambi et al., 2003). C. albicans also binds complement regulators, including C4b-binding protein (C4BP), a classical pathway inhibitor (Meri et al., 2004), factor H, and FHL-1 (Meri et al., 2002). Both yeast and hyphal forms bound C4BP, with a prominent binding site being the tip of germ tubes. C4BP was found to bind to the same ligand as FHL-1 (an alternative pathway inhibitor) (Meri et al., 2004). Binding of the complement regulators is suggested to inhibit complement activation at the fungal cell surface, but also enhances binding to endothelial cells (Meri et al., 2004). C. albicans hyphae are also able bind to epithelial cells via vitronectin (Santoni et al., 2001) and to induce endocytosis into endothelial cells via N-cadherin (Phan et al., 2005). Endocytosis may also be stimulated via C. albicans phosphorylating two endothelial cell proteins (Belanger et al., 2002).

C. albicans mutant strains unable to damage endothelial cells in vitro were found to be attenuated in virulence in vivo (Sanchez et al., 2004). This may be due, in part, to differential inflammatory responses noted for C. albicans strains with different invasive potentials in epithelial and endothelial cells, with highly invasive strains triggering higher levels of proinflammatory cytokines (Villar et al., 2005).

Interactions with the different host cell receptors explain the various observations found for C. albicans influencing cytokine responses. C. albicans cells with defects in mannosylation, hence differential signalling via the mannose receptor and TLR4, were shown to stimulate lower levels of cytokine production in mononuclear cells or murine macrophages (Netea et al., 2006). C. albicans yeast cells were found to stimulate large amounts of IFN-y in PBMCs or murine splenic lymphocytes, but hyphal cells did not (van der Graaf et al., 2005). This again reflects the differences in signalling found for the different morphological forms.

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Cure Your Yeast Infection For Good

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