Dendritic Cell Interaction with Candida albicans Critically Depends on N-Linked Mannan

Abstract

The fungus Candida albicans is the most common cause of mycotic infections in immunocompromised hosts. Little is known about the initial interactions between Candida and immune cell receptors, because a detailed characterization at the structural level is lacking. Antigen-presenting dendritic cells (DCs), strategically located at mucosal surfaces and in the skin, may play an important role in anti-Candida protective immunity. However, the contribution of the various Candida-associated molecular patterns and their counter-receptors to DC function remains unknown. Here, we demonstrate that two C-type lectins, DC-SIGN and the macrophage mannose receptor, specifically mediate C. albicans binding and internalization by human DCs. Moreover, by combining a range of C. albicans glycosylation mutants with receptor-specific blocking and cytokine production assays, we determined that N-linked mannan but not O-linked or phosphomannan is the fungal carbohydrate structure specifically recognized by both C-type lectins on human DCs and directly influences the production of the proinflammatory cytokine IL-6. Better insight in the carbohydrate recognition profile of C-type lectins will ultimately provide relevant information for the development of new drugs targeting specific fungal cell wall antigens.

Schistosomamansonitriggers Dectin-2, which activates the Nlrp3 inflammasome and alters adaptive immune responses

“…For example, helminth-induced regulatory T cells have been shown to provide beneficial immunosuppressive effects in mouse models of Western illnesses such as asthma and diabetes (35,36). However, helminth-derived components are equally adept at immunomodulating innate responses and, in confirmation with other studies (6, 11), we show here that SEA can indeed suppress TNF-α and IL-6 secretion from TLR-triggered DCs.…”

“…Another mode of activation was elicited from inhibition studies using silica, which elucidated that lysosomal acidification and lysosomal damage caused the release of cathepsins into the cytoplasm after particle uptake (19). In the studies described here, blocking phagocytosis by cytochalasin D did not alter SEAmediated IL-1β release and neither did experiments using mice deficient in the phagocytosis-inducing mannose receptor (35). Interestingly, as previously described with Candida albicans (22) and the Plasmodium-derived hemozoin crystals (23), Syk-kinase signaling is also required for SEA-mediated Nlrp3 inflammasome activation.…”

Dectin-2 is a Syk-coupled pattern recognition receptor crucial for Th17 responses to fungal infection

“…ND, not detectable. Taylor et al, 2004;Cambi et al, 2008). Dectin-2 may fall in the same group, although competition studies suggest that the molecular pattern recognized by Dectin-2 is distinct from that bound by SIGNR-1 and mannose receptor (McGreal et al, 2006).…”

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…150 Interestingly, N-linked mannan, but not O-linked or phosphomannan, is specifically recognized by DC-SIGN on human DCs and directly influences the production of the proinflammatory cytokine IL-6. 151 Galectin-3 on murine bone marrow-derived DCs was recently found to be able to modulate Th17 responses to C. albicans. 152 Galectin-3 is encoded by GAL3 gene.…”