PRR ligation of Candida
pathogen-associated molecular patterns results in the activation of intracellular signaling pathways, leading to transcriptional activation of genes in the nucleus and, ultimately, the production of novel proteins (). Initiation of signaling involves several potential mechanisms, depending on the PRR (Ivashkiv, 2008
; Kenny and O’Neill, 2008
; O’Neill, 2008
; Tsoni and Brown, 2008
). TLRs, for example, contain a Toll/IL-1 receptor domain in their cytoplasmic region that interacts with adaptor proteins—most commonly, MyD88 (myeloid differentiation 88) but also TRIF (Toll/IL-1 receptor domain–containing adapter-inducing interferon β), TRAM (TRIF-related adaptor molecule), and MAL (MyD88 adapter-like protein). This interaction leads to the activation of the IRAK (IL-1 receptor-associated kinase) proteins and TRAF6 (TNF receptor-associated factor 6). In turn, this leads to activation of the NF-κB and MAPK pathways (respectively, nuclear factor kappa light chain enhancer of activated B cells and mitogen-activated protein kinase), as well as IRF (interferon regulatory factor) signaling via IRF 3, 5, and 7.
Fig. 1. Signal pathway activation by different surface PRRs. All known PRRs activate MAPK and NF-κB signal pathways but may differ in the extent to which they activate these pathways or which combination of these pathways are activated, thus allowing (more ...)
The MAPK pathways constitute 3 arms: p38, JNK (c-Jun N-terminal kinase), and ERK1/2 (extracellular signal-regulated kinase 1/2). However, C-type lectin receptors are thought to signal through activation of ITAM/ITIM cytoplasmic domains (immunoreceptor tyrosine-based activation/inhibition motif)—through their own (e.g., dectin-1) or through a coreceptor, such as DAP12 (DNAX activation protein of 12 kDa) and FcRγ (Fc gamma chain receptor; e.g., dectin-2). Ligation of these receptors leads to activation of a different set of early adaptors— predominantly, Src family kinases such as Src, Lyn, and Fyn. In the case of dectin-1, this leads to activation of Syk kinase and the downstream activation of the CARD9/Bcl10/MALT1 signaling complex (caspase recruitment domain family/B-cell CLL-lymphoma 10/mucosa-associated lymphoid tissue lymphoma translocation gene 1). Irrespective of the C-type lectin receptor pathways and adapters used, the result is the activation of the NF-κB and MAPK pathways.
Further regulation of these pathways is achieved by activation of other signal-associated proteins. For example, specific regulation of MAPK responses occurs via the action of dual specificity phosphatases, also known as MKPs (MAPK phosphatases; Liu et al., 2007
). In the case of ITIM activation, the SHP protein tyrosine phosphatases are activated, which generally suppresses signaling. Which of these pathways and proteins are induced depends on the PRR activated and the heterogeneity of responses generated by the different PRRs will manifest through differences in the activation of alternative elements of these pathways. For example, one pathway may lead to the activation of p38 and JNK but not ERK1/2 MAPK signaling, whereas another may lead to JNK and ERK1/2 but not p38 signaling, with similar differences in the NF-κB elements activated. However, irrespective of the signal pathways activated, there may be cell-specific differences resulting from different expression levels of the various proteins. The majority of studies defining the PRR-mediated pathways were performed using myeloid or lymphoid cells, but detailed analysis of PRR-mediated pathways in other cell types—specifically, epithelial cells—may yet identify novel and unusual mechanisms of pathogen recognition and control at mucosal surfaces.
To this end, the majority of epithelial cell work has been bacterial based and has identified NF-κB and MAPK as the main pathways activated (Kinane et al., 2008
; Handfield et al., 2008
). NF-κB is also thought to be a likely signaling candidate in the activation of epithelial cells to Candida
(Pivarcsi et al., 2003
; Roeder et al., 2004b
). However, in a recent study using oral epithelial cells we demonstrated that the innate response to C. albicans
is via both NF-κB and MAPK pathways (Moyes et al., 2010
). We found that NF-κB activation appears to be independent of morphology and results from generic recognition of fungal moieties present on all Candida
spp. and, probably, fungi in general. The MAPK network appears to elicit the “danger response” and is dependent on hyphal recognition and fungal dose. Further detailed characterization of these signaling pathways in epithelial cell types is required, which will advance our understanding of how human mucosal surfaces recognize, respond to, and control these important fungal pathogens.