C-type lectin receptors orchestrate antifungal immunity

Abstract

Immunity to pathogens critically requires pattern-recognition receptors (PRRs) to trigger intracellular signaling cascades that initiate and direct innate and adaptive immune responses. For fungal infections, these responses are primarily mediated by members of the C-type lectin receptor family. In this Review, we highlight recent advances in the understanding of the roles and mechanisms of these multifunctional receptors, explore how these PRRs orchestrate antifungal immunity and briefly discuss progress in the use of these receptors as targets for antifungal and other vaccines.

Figure 1

Structure of the fungal cell wall. By EM, the various carbohydrate-rich layers of the fungal cell wall (in this example C. albicans) can be observed, which consist of mannan (mannosylated proteins), β-glucan and chitin, as indicated. Although providing a rigid framework, which gives these pathogens their shape and protection from the environment, the cell wall is a dynamic structure which changes significantly, particularly during the morphological transitions that many fungi can undergo (yeast to hyphae, for example). Furthermore, some of the internal components, such β-glucans, can be exposed on the fungal surface in specific areas, such as the bud scar in C. albicans. The composition of the cell wall also varies between different fungal species. Several CLR have been identified which recognize these cell-wall structures, including transmembrane and soluble CLRs. The latter group, consisting of Surfactant Protein (SP)-A, SPD and mannose-binding lectin (MBP), opsonise fungi and facilitate their recognition, but were not discussed in the text (For a review of these molecules see Vautier et al. 2012). The micrograph was kindly provided by Jules Ene and Neil Gow.

Figure 2

Transmembrane CLRs involved in antifungal immunity and their intracellular signaling pathways. Dectin-1, Dectin-2 and Mincle induce intracellular signaling via tyrosine (Y)-based activation motifs (immunoreceptor tyrosine-based activation motifs or ITAMs) which recruit and activate Syk-kinase either directly, or indirectly through the FcγR adaptor chain. Signaling through protein-kinase C (PKC)δ, this pathway activates the Card9-Bcl10-Malt1 complex inducing gene transcription and the production of various inflammatory mediators. DC-SIGN and Dectin-1 can signal via the Raf-1 kinase pathway which modulates (dotted line) other signaling pathways, including those induced by the Toll-like receptors (TLR) and the Dectin-1/ Syk pathway. The mannose receptor (MR) can also induce intracellular signaling, but the mechanisms involved are unknown. CLR signaling can collaborate with that of the TLR (red bi-arrow), to synergistically induce or repress the induction of various cytokines and chemokines. CLR can also mediate fungal phagocytosis and induction of anti-microbial effector mechanisms (not shown).

Figure 3

Integration of CLR -mediated signaling directs adaptive immunity. CLR-mediated recognition of fungi drives their uptake and killing by phagocytes, and directs the development of protective Th1/Th17 responses. Induction of IL-12 drives IFN-γ production by Th1 and iNKT cells, which is critically required for the activation of phagocytes. Remarkably, production of IFN-γ by self-reactive iNKT cells occurs following CLR-mediated induction of IL-12 on antigen-presenting cells. On the other hand, induction of IL-1β, IL-6, and IL-23 promotes Th17 differentiation, which drives the production of IL-17 and IL-22. These cytokines are critically required for neutrophil recruitment and epithelial antimicrobial peptide (AMP) production and provide protection against fungal infections, particularly at the mucosa. Notably, the production of IL-17 can also be directly induced by CLRs expressed on γδ T cells, without TCR triggering.

Figure 4

CLRs mediate inflammasome activation. Fungi can activate the NLRP3 and NLRC4 inflammasomes, inducing the caspase-1-mediated cleavage of pro-IL-1β and production of bioactive IL-1β. While CLR, such as Dectin-1, can drive the induction of pro-IL-1β, it is unclear how the intracellularly-located NLR actually sense fungi. Activation of these receptors may directly involve CLR, as this process was found to require Syk kinase (as well as fungal uptake, the respiratory burst and potassium efflux). More recently, Dectin-1 has been shown to be able to activate the noncanonical caspase-8 inflammasome, which interacts directly with the Card9-Bcl-10-MALT1 complex. Activation of caspase-8 by recruitment to this signaling complex results in the cleavage of pro-IL-1β. Assembly of these inflammasomes also involves other components, including ASC (not shown).