The Immunomodulatory Effects of Mannan on the Fungicidal Activity of Macrophages Against Candidozyma auris Bloodstream Infection Associated with the GPCR-PI3K-NF-κB Signaling Pathway

Candidozyma auris is an emerging multidrug-resistant fungal pathogen, which causes high mortality and nosocomial outbreaks worldwide. Macrophages are key innate immune cells that clear fungi through phagocytosis, reactive oxygen species, and cytokine secretion. Mannan, a major fungal cell wall polysaccharide, has immunomodulatory properties and can interact with receptors such as C-type lectins and Toll-like receptors 2/4, which are associated with nuclear factor kappa-light-chain-enhancer of activated B cells and mitogen-activated protein kinase signaling in macrophages. However, its role in host defense against C. auris remains unclear. In this study, the effects of mannan against C. auris infection were evaluated using Ana-1 macrophages and murine models. Cell Counting Kit-8 assay, neutral red uptake, and fluorescence microscopy assay showed that mannan with safety concentrations of 0–160 μg/mL significantly increased the phagocytosis activity of Ana-1 macrophages, and following pre-stimulation of Ana-1 macrophages with mannan for 1 h, the phagocytic ability of these macrophages to C. auris was significantly enhanced at 30 min, and the killing ability was significantly higher than that of the control group at 4 h. Transcriptomic analysis combined with real-time quantitative PCR and Western blotting showed that mannan enhanced the immune response of Ana-1 macrophages, which was associated with changes in GPCR-related PI3K/NF-κB signaling, and improved their killing activity against C. auris. In vivo efficacy was further validated in mice and zebrafish via fungal burden, histopathology, and immune cell recruitment assays, which confirmed that mannan can effectively prevent C. auris bloodstream infection. These findings provide insights into mannan’s immunomodulatory mechanisms and support its potential in developing new antifungal immunotherapies for C. auris infection.