C-Type Lectin Receptors in Innate Antifungal Immunity

C-Type lectin receptors (CLRs) constitute a family of pattern recognition receptors expressed primarily on myeloid cells that detect carbohydrate moieties on fungal cell walls. Through recognition of β-glucans, mannans and other complex polysaccharides, CLRs initiate intracellular signalling cascades involving Syk kinase, the adaptor CARD9 and downstream transcription factors such as NF-κB and IRF5. These pathways coordinate phagocytosis, reactive oxygen species generation, cytokine production and antigen presentation, bridging innate and adaptive immunity. CLR engagement also shapes the balance between pro-inflammatory and regulatory responses, contributing to host defence while preventing excessive tissue damage. Emerging evidence highlights the capacity of certain CLRs to undergo homo- and hetero-dimerisation, modulating ligand affinity and signalling outcomes. Defects in CLR-mediated recognition, whether through genetic polymorphisms or pathway disruption, underpin increased susceptibility to invasive fungal infections and inform therapeutic strategies aimed at enhancing antifungal immunity.

Research from Nature Portfolio

Recent studies have revealed that individual CLRs can form distinct receptor complexes to fine-tune antifungal responses. One investigation demonstrated that a specific CLR isoform assembles as homodimers or heterodimers with a Toll-like receptor, leading to enhanced binding of fungal β-glucans and selective suppression of IRF5-driven IL-12 production. This receptor pairing promotes ubiquitin-mediated degradation of a key adaptor protein, thereby restraining pro-inflammatory cytokine release and influencing NK cell activity during Candida infection. Genetic ablation of this CLR variant in murine models confers increased resistance to systemic candidiasis by unleashing IL-12–mediated natural killer cell responses, illustrating how receptor dimerisation can serve as a checkpoint in innate antifungal defences.

C-Type Lectin Receptors in Innate Antifungal Immunity publication trend

The graph below shows the total number of articles in c-type lectin receptors in innate antifungal immunity across all publications each year (not limited to Nature Index journals).

Technical terms

C-Type Lectin Receptor (CLR): A class of carbohydrate-binding receptors on innate immune cells that recognise fungal cell wall polysaccharides and initiate downstream signalling.

β-Glucan: A polysaccharide component of fungal cell walls that serves as a key ligand for several CLRs, triggering immune activation.

Homodimerisation/Heterodimerisation: The association of two identical or different receptor molecules, respectively, altering ligand affinity and signalling.

CARD9: An intracellular adaptor protein that couples Syk-activated CLRs to canonical NF-κB pathways, essential for antifungal cytokine production.

Ferroptosis: A regulated form of iron-dependent cell death characterised by lipid peroxidation, implicated in the loss of myeloid-derived suppressor cell function during infection.

Trained Immunity: The enhanced responsiveness of innate immune cells to subsequent stimuli, induced by initial exposure to microbial components such as β-glucans.

References

1. Myeloid C-type lectin receptors in innate immune recognition. Immunity (2024).
2. C-type lectin receptor 2d forms homodimers and heterodimers with TLR2 to negatively regulate IRF5-mediated antifungal immunity. Nature Communications (2023).
3. Mitochondria-mediated ferroptosis induced by CARD9 ablation prevents MDSCs-dependent antifungal immunity. Cell Communication and Signaling (2024).
4. Dectin-1 Signaling Update: New Perspectives for Trained Immunity. Frontiers in Immunology (2022).
5. Syk Kinase-Coupled C-type Lectin Receptors Engage Protein Kinase C-δ to Elicit Card9 Adaptor-Mediated Innate Immunity. Immunity (2012).