Candida albicans interactions with epithelial cells and mucosal immunity

Abstract

Candida albicans interactions with epithelial cells are critical for commensal growth, fungal pathogenicity and host defence. This review will outline our current understanding of C. albicans-epithelial interactions and will discuss how this may lead to the induction of a protective mucosal immune response.

Figure 1. Stages of C. albicans oral infection

The progression of C. albicans infection of oral epithelial cells is characterised by three distinct stages (from left to right): adhesion, invasion via two different routes (active penetration and induced endocytosis), and tissue damage. (A) Scanning and transmission electron micrographs and histology of epithelial tissue (kindly provided by Holland, Özel, Zakikhany, Schaller, Wächtler, Hube). (B) Schematic drawing of the three distinct stages including factors and activities that are involved. Examples of genes necessary for each activity are in brackets. SAPs - secreted aspartic proteases.

Figure 2. Signalling pathways that discriminate between Candida albicans yeast and hyphae

Oral epithelial cells are able to discriminate between the two morphological forms of C. albicans via the MAPK pathway using a biphasic response. In the first response, a colonising yeast cell is recognised by an as yet undetermined Pattern Recognition Receptor (PRR) resulting in activation of the NF-κB pathway and weak, early and transient activation of all three MAPK pathways (p38, ERK1/2 and JNK). This results in activation of p65/p50 heterodimer transcription factor activity (NF-κB) and activation of c-Jun DNA binding via the ERK1/2 and JNK pathways. What role, if any, is played by p38 at this point is unknown. Hyphal cells present at low dose also activate this first response. In the second phase, when in sufficient quantities, C. albicans hyphae are recognised by an unknown mechanism that results in continued activation of the NF-κB pathway along with further, stronger activation of the MAPK pathways – in particular p38 and ERK1/2. Activation of p38 leads to activation of the c-Fos transcription factor, which, in conjunction with the p65/p50 NF-κB heterodimers, results in upregulation of cytokine and inflammatory mediator expression. At the same time, activation of ERK1/2 signalling results in stabilisation of the MKP1 phosphatase, which targets p38 and JNK to deactivate them, hence acting as part of a negative feedback loop and preventing a potentially deleterious over-reaction of the immune system.

Figure 3. Model of mucosal protection against Candida albicans infection

Infection and subsequent invasion of the epithelial surface by C. albicans hyphae results in the production of cytokines and chemokines in a dose dependent fashion as described in the text and in the legend to Fig. 2. Secreted chemokines, particularly IL-8, will recruit neutrophils (polymorphonuclear leukocytes (PMN)) from the circulating blood to the infected epithelium. Here, EC-secreted cytokines (e.g. GM-CSF) will further activate the PMNs and induce them to secrete their own cytokines, including TNFα, which then act on the local epithelial cells causing upregulation of TLR4 and potentially other mediators. TLR4 upregulation induces a protective/resistance phenotype and promotes clearance of the invading fungus by an as yet unknown mechanism.

Figure 4. Cytokine/chemokine network induced during C. albicans infection of mucosal epithelium

Infection of epithelial cells by C. albicans results in the production of cytokines (blue) and chemokines (red) which recruit and activate various other immune cells. The best documented of these networks is initiated by IL-8. IL-8 recruits circulating neutrophils (PMNs) that are then activated by a variety of cytokines including GM-CSF, G-CSF and IL-1 family members. Activated PMNs then produce TNFα which then affect epithelial gene transcription. TGFβ is produced constitutively by epithelial cells and will act with IL-1β and IL-6 to induce T cell differentiation to the Th17 phenotype. Mucosal homing cells including Th17 T cells and activating dendritic cells will also be recruited by the increased expression of CCL20 and β-defensin 2, acting through the CCR6 receptor. This will lead to the presence of active Th17 T cells in the region to combat the fungal infection. CCL20 and β-defensin 2 will also recruit in Treg cells which will act to suppress and control the Th17 response. Finally, infection of epithelial cells leads to the production of IL-20 family cytokines including IL-19, IL-20 and IL-24. These cytokines will function in an autocrine fashion, although their role in fungal immunity is not fully understood.