Differential Adaptation of Candida albicans In Vivo Modulates Immune Recognition by Dectin-1

Abstract

The β-glucan receptor Dectin-1 is a member of the C-type lectin family and functions as an innate pattern recognition receptor in antifungal immunity. In both mouse and man, Dectin-1 has been found to play an essential role in controlling infections with Candida albicans, a normally commensal fungus in man which can cause superficial mucocutaneous infections as well as life-threatening invasive diseases. Here, using in vivo models of infection, we show that the requirement for Dectin-1 in the control of systemic Candida albicans infections is fungal strain-specific; a phenotype that only becomes apparent during infection and cannot be recapitulated in vitro. Transcript analysis revealed that this differential requirement for Dectin-1 is due to variable adaptation of C. albicans strains in vivo, and that this results in substantial differences in the composition and nature of their cell walls. In particular, we established that differences in the levels of cell-wall chitin influence the role of Dectin-1, and that these effects can be modulated by antifungal drug treatment. Our results therefore provide substantial new insights into the interaction between C. albicans and the immune system and have significant implications for our understanding of susceptibility and treatment of human infections with this pathogen.

Neither Dectin-2 nor the Mannose Receptor Is Required for Resistance to Coccidioides immitis in Mice

“…Robinson et al found that BMDC from B6 mice required only 1 of the two Dectin receptors in order to make TNF-␣ and IL-10 in response to zymosan (83), implying that the function of the two receptors was redundant if a fungal particle is recognized by both receptors. Mutation of either receptor makes mice more susceptible to systemic Candida albicans infection, though this may depend on the strain of C. albicans used to infect the mice (31,84,85).…”

Immunity against fungi

“…Loss of individual CLRs results in variable susceptibility to C. albicans (22,23) and A. fumigatus (24,43), in part due to strain-specific differences in CLR activation, as shown for C. albicans (59). Consistent with SYK/CARD9 being central for CLR signal integration, mice with hematopoietic or DC-specific Syk deletion or with global CARD9 deficiency are highly susceptible to C. albicans (29,60) and A. fumigatus (43) challenge.…”

The Transmembrane Adaptor Protein SCIMP Facilitates Sustained Dectin-1 Signaling in Dendritic Cells

“…Through its carbohydrate recognition domain, it specifically recognizes ␤-1,3-glucan (5), which is a typical component of fungal cell walls (6). Dectin-1 is considered a major receptor for ␤-glucans and plays an important role in the defense against various species of pathogenic fungi in mice, including Candida albicans, Aspergillus fumigatus, and Pneumocystis carinii (7)(8)(9)(10)(11). The importance of dectin-1 for antifungal defense has also been demonstrated by studies of human patients with disrupted dectin-1 function who display increased mucosal colonization with Candida species and suffer from recurrent mucocutaneous fungal infections (12,13).…”