Candida albicans N-Linked Mannans Potentiate the Induction of Trained Immunity via Dectin-2

The interaction between the Candida albicans cell wall and pattern recognition receptors is crucial for the initiation of host immune responses, which, ultimately, contribute to the clearance of this pathogenic fungus. In the present study, we investigate the ability of C. albicans mannans to modulate immune response and induce innate immune memory (also termed trained immunity). Using mutants of C. albicans that are defective in or lack mannosyl residues, we show that alterations in the mannosylation of the C. albicans cell wall affect the innate cytokine response and strongly reduce the secretion of T-cell-derived cytokines. Subsequently, we demonstrate that the branching of N-linked mannan, but not O-linked mannan, is essential to potentiate the induction of trained immunity, a process mediated by dectin 2. In conclusion, N-linked mannan is needed, in addition to beta-glucans, for an effective induction of trained immunity by C. albicans. This study investigates the role of mannosylation of Candida albicans cell wall in innate immune responses. Recognition of N-linked mannans, particularly the alpha 1,6-mannose backbone, by dectin 2 is shown to be crucial for cytokine production and induction of trained immunity.