The role of dendritic cells in the innate recognition of pathogenic fungi (A. fumigatus, C. neoformans and C. albicans)

Figures & data

Figure 1. Pattern recognition receptors on DCs and signaling pathways that prime T cell differentiation. Recognition of C. neoformans, C. albicans and A. fumigatus mediates by detection of fungal pathogen-associated molecular patterns via Toll-like receptors (TLRs) in the cell surface or endosomes and C-type lectin receptors (CLRs). This graphic represents the TLRs and CLRs responsible for the detection of C. albicans, C. neoformans and A. fumigatus expressed on DCs and the signaling pathways involved in the antifungal response.

Figure 2. DC mediated responses to fungal pathogens. Conventional DCs are characterized by CD11b⁺, CD11c^HI, Ly6C^Hi and CCR2⁺. These cDCs express the surface TLRs (TLR1, TLR2, TLR4 and TLR6) and the CLRs (Dectin1, Dectin2 and DC-SIGN). Upon recognition of the fungal pathogen, cDCs activate a series signaling cascades that result in: (1) phagocytosis of the fungal pathogen, (2) uptake to lysosomal compartments where the pathogen is killed and antigens can be loaded into MHC for presentation to T cells, (3) Secretion of cytokines and chemokines responsible for communicating with other cells to induce a host response and (4) induce the proper Th response. pDCs express the endosomal TLRs (TLR7 and TLR9), FcRγ and possibly the CLR Dectin2. pDCs are responsible for: (1) detection of exogenous DNA and RNA resulting in the induction of an inflammatory response, (2) orchestrating Th cell responses and (3) direct killing of A. fumigatus hyphae.

Table 1. Polymorphisms associated with susceptibility to fungal infections

Gene	SNP or haplotype	Effect	Disease outcome	References
TLR1	TLR1 293G > C TLR1 743A > G	Unknown	Susceptibility to invasive aspergillosis	31
TLR3	TLR3 95C > A	Defective CD8^+ T cell proliferation	Susceptibility to IA	35
TLR4	TLR4 1063A > G TLR4 1363C > T	Impaired ligand-binding domain	Susceptibility to IA, A. fumigatus colonization, chronic cavitary pulmonary aspergillosis, systemic C. albicans infection	33, 83, 90 and 95
TLR6	TLR6 745C > T	Unknown	Susceptibility to IA	31
TLR9	TLR9 T1237C	Increased NFκB binding	Susceptibility to allergic bronchopulmonary asperillosis	33
Dectin1	Dectin1 Y223S	Decreased Zymosan Binding	Resistance to oropharyngeal candidiasis	95
	Dectin1 Y238X	Decreased surface expression, β-glucan binding and cytokine production	Susceptibility to chronic mucocutaneous candidiasis, C. albicans colonization, IA	30, 91 and 93
CARD9	CARD9 Q295X	Decreased Th17	Susceptibility to mucocutaneous candidiasis	92
CXCL10	+11101C/+1642G/-1101A	Decreased chemokines by DCs following A. fumigatus exposure	Susceptibility to IA	94

* This table has been adapted from Romani et al.²⁰

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