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

TLDR

Candida albicans is the leading cause of fungal infections in immunocompromised patients, yet the early interactions between its cell wall components and dendritic cell receptors remain poorly characterized. The study aims to elucidate how dendritic cell C‑type lectins recognize Candida albicans carbohydrates to inform drug development targeting fungal cell wall antigens. The authors found that DC‑SIGN and the macrophage mannose receptor mediate Candida albicans binding and uptake, and that N‑linked mannan is the specific carbohydrate recognized by these lectins, driving IL‑6 production.

Abstract

The fungus <i>Candida albicans</i> is the most common cause of mycotic infections in immunocompromised hosts. Little is known about the initial interactions between <i>Candida</i> 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-<i>Candida</i> protective immunity. However, the contribution of the various <i>Candida</i>-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 <i>C. albicans</i> binding and internalization by human DCs. Moreover, by combining a range of <i>C. albicans</i> glycosylation mutants with receptor-specific blocking and cytokine production assays, we determined that <i>N</i>-linked mannan but not <i>O</i>-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.