Pattern recognition receptors in fungal immunity

Abstract

Over the last decade, invasive fungal infections have emerged as a growing threat to human health worldwide and novel treatment strategies are urgently needed. In this context, investigations into host-pathogen interactions represent an important and promising field of research. Antigen presenting cells such as macrophages and dendritic cells are strategically located at the frontline of defence against potential invaders. Importantly, these cells express germline encoded pattern recognition receptors (PRRs), which sense conserved entities from pathogens and orchestrate innate immune responses. Herein, we review the latest findings regarding the biology and functions of the different classes of PRRs involved in pathogenic fungal recognition. We also discuss recent literature on PRR collaboration/crosstalk and the mechanisms involved in inhibiting/regulating PRR signalling. Finally, we discuss how the accumulated knowledge on PRR biology, especially Dectin-1, has been used for the design of new immunotherapies against fungal infections.

Keywords: C-type lectin-like receptor; Crosstalk; Nod-like receptor; Pathogen recognition receptor; Toll-like receptor.

Fig. 1

PRR signalling pathways. (A) Following TLR-mediated ligand recognition, MyD88 is recruited to the TLR and a signalling cascade involving IRAK-4, IRAK-1/2, TRAF6, TGF-β-activated kinase 1 (TAK-1), TAK1-binding protein 1 (TAB1), TAB2, TAB3 complex and IκB kinase (IKK)-β is initiated. IKK-β phosphorylates the NFκB inhibitory protein, IκBa, causing its degradation thereby facilitating NFκB nuclear translocation and transcription of proinflammatory cytokines. TLR3, 4, 7, 9, 10 and 13 signal in endosomes via the TRIF-dependent pathway. Ligand-induced TLR activation initiates a TRIF, TRAF3, TBK1 and IRF-3 cascade. Alternatively, TRIF can activate a TRAF6, RIP1, TRADD, TAK-1, NFκB pathway. (B) CLRs signal either by associating with the ITAM-containing FcRγ signalling chain (Dectin-2, Mincle, Mcl) or through a hemITAM in its cytoplasmic tail (Dectin-1). Following ligand recognition, the hemITAM/ITAM are phosphorylated and Syk is recruited. A signalling cascade involving PLCγ, PKCδ and a Card9/Bcl10/Malt1 complex is then initiated. This leads to IKKβ-mediated degradation of IκB to induce nuclear translocation of NFκB (p50, p65). MAPK pathways (ERK, p38 and Jnk) are also activated downstream of PLCγ to induce subsequent AP-1 activation. (C) NLRP3 inflammasome is activated via a CLR-Syk pathway. NLRP3 recruits ASC and pro-Caspase-1 to form an inflammasome complex. This leads to caspase-1 activation and Caspase-1-mediated cleavage of pro-IL-1β into functional IL-1β. Additionally, non-inflammasome forming NLRs such as NOD1 and NOD2 signal via RIP2 to activate the NEMO-IKBα-IKKβ complex to induce p50, p65, IκB and subsequent NFκB activation. In addition, a CARD9-MAPK pathway (ERK, p38 and Jnk) is activated resulting in subsequent AP-1 activation. (D) MDA5 activation by viral RNA, signals through IPS-1 to activate IRF3 and TBK-1, which in turn activates NFκB to induce IFN-β. Whether this occurs in response to fungal pathogens remains to be determined.

Fig. 2

PRR collaboration. (A) F. pedrosoi engages Mincle to induce a weak TNF response however artificial engagement of a TLR such as TLR2 by Pam₃CSK₄ induces a more robust TNF response. (B) F. monophora is recognised by Mincle and leads to CARD9-BCL-10-MALT-1 complex formation through SHP2-Syk activation. This leads to PI3K activation and AKT phosphorylation, rather than NFκB activation. AKT phosphorylates MDM2, which promotes translocation to the nucleus. MDM2 associates with Dectin-1- or LPS-induced IRF1 and the ubiquitin ligase activity of MDM2 is activated. MDM2 targets IRF1 for degradation thereby blocking IL-12p35 activation. (C) Malassezia spp. and H. capsulatum activate Dectin-1 and Dectin-2 in a Syk-dependent manner to induce NLRP3-mediated IL-1β production through Caspase-1 and ASC signalling to induce Th1/Th17 responses.

Fig. 3

Negative Regulation of PRR-induced signalling. (A) Dectin-1 binds β-glucan particles (such as yeasts) to form the “phagocytic synapse”. The physical interaction between particulate β-glucan and Dectin-1 results in exclusion of CD45 and CD148 tyrosine phosphatases from the synapse. This facilitates Dectin-1 signalling via Src/Syk activation. Soluble β-glucans are unable to exclude the tyrosine phosphatases from the synapse therefore Dectin-1 signalling is blocked by the inhibitory activity of CD45 and CD148. (B) CLR activation results in their ubiquitination and degradation in a Syk-dependent manner. Cbl-b mediates ubiquitination of the activated CLRs through Syk. The ubiquitinated CLRs are then sorted into lysosomes for degradation by an endosomal sorting complex required for transport (ESCRT) system. Additionally, Cbl-b has been shown to target MyD88 and TRIF for degradation following phsophorylation by Syk. Lastly, Cbl-b potentially targets NLRP3 for degradation. (C) C. albicans is recognised by Dectin-1, leading to activation of NFAT and Jnk1. NFAT induces CD23 expression and production of nitric oxide. In the absence of Jnk1, NFAT activation, CD23 and nitric oxide levels are increased compared to WT cells. (D) β-glucans induce expression of miR-146a via a Dectin-1-Syk-NFκB pathway. MiR-146a negatively regulates Dectin-1 signalling by supressing NFκB activation.