Mucosal immunity and Candida albicans infection

Abstract

Interactions between mucosal surfaces and microbial microbiota are key to host defense, health, and disease. These surfaces are exposed to high numbers of microbes and must be capable of distinguishing between those that are beneficial or avirulent and those that will invade and cause disease. Our understanding of the mechanisms involved in these discriminatory processes has recently begun to expand as new studies bring to light the importance of epithelial cells and novel immune cell subsets such as T(h)17 T cells in these processes. Elucidating how these mechanisms function will improve our understanding of many diverse diseases and improve our ability to treat patients suffering from these conditions. In our voyage to discover these mechanisms, mucosal interactions with opportunistic commensal organisms such as the fungus Candida albicans provide insights that are invaluable. Here, we review current knowledge of the interactions between C. albicans and epithelial surfaces and how this may shape our understanding of microbial-mucosal interactions.

Figure 1

Signal pathway activation by the main TLR and CLR receptors that detect Candida. Signalling through TLRs proceeds mainly via TRAF6 with a variety of adaptor proteins acting as intermediaries between receptor and TRAF6. Foremost among these is MyD88 which is utilised by all known TLRs except TLR3. As well as MyD88, there are other adaptor molecules, including TRIF, MAL, and TRAM, with the different TLRs using different combinations of these adaptors. Activation of these adaptors leads to activation of IRAK1, 2, and 4 followed by ubiquitination of TRAF6 which leads to subsequent activation of downstream signalling pathways. Signalling through CLRs utilises cytoplasmic ITAM domains to interact with the SYK adaptor molecule, activating the Card-9-Bcl10-Malt1 protein complex. Some CLRs, such as Dectin-1, include a modified ITAM domain in their cytoplasmic domain. Others, such as Dectin-2, associate with other receptor molecules, notably the FcRγ and DAP12 proteins, which possess the ITAM domain that transduces the signal into the cell. In all cases, the net effect is to activate the MAPK and NF-κB pathways, leading to upregulation of specific gene transcription. In addition to this, TLRs are also known to activate transcription via members of the IRF family, including IRF3, IRF5, and IRF7.

Figure 2

Epithelial cell recognition of C. albicans. Epithelial cells recognise C. albicans via a two-step process [40]. Initial recognition of yeast by surface PRRs results in prolonged activation of NF-kB and an early transient activation of MAPK signalling leading to activation of c-Jun through the ERK1/2 and JNK pathways. When the burden of hyphae passes a threshold, recognition of these hyphae triggers a second, prolonged activation of MAPK signalling. This results in activation of MKP1 through the ERK1/2 pathway and c-Fos via p38 signalling. NF-κB and c-Fos then play essential roles in the transcription of cytokines secreted by the epithelial cells, whilst MKP1 acts as a negative regulator to control the activation of JNK and p38 signalling.