The Candida albicans factor MNN9 modulates cytokine production in distinct epithelial cell types

The opportunistic fungal pathogen Candida albicans colonizes mucosal surfaces of the majority of healthy human individuals. However, the fungus can cause superficial infections in otherwise healthy people and could develop life-threatening systemic candidiasis in immunocompromised patients. Mucosal epithelial cells can discriminate between the commensal and pathogenic lifestyle of C. albicans by the activation of a biphasic MAPK mediated by pattern recognition receptors resulting in a cytokine response. This study aimed to compare the cytokine release from oral mucosal epithelial cells with parenchymal hepatic and renal epithelial cells. As a result, C. albicans infection caused epithelial damage with susceptibility differing between cell lines, and induced an innate immune response by a core secretion of the inflammatory cytokines IL-6 and IL-8, and additionally by the secretion of cell line-specific cytokines. Furthermore, the epithelial immune response can be modulated by C. albicans factors that was observed during a large-scale host response screening. This study focused on Mnn9 that is crucial for the N-mannosylation of the cell wall and therefore has an influence on host recognition. A deletion in the MNN9 gene induced stronger inflammatory cytokine releases by hepatic and oral epithelial cells without altering the damage potential, suggesting differences in the activation of MAPK signaling. Indeed, while the MNN9 mutant induced a delayed activation of oral MKP1, ERK1/2 and JNK, consistent phosphorylation indicates stronger and prolonged activation of all three MAPK pathways during infection that could explain the increased cytokine release. Taken together, this study could show that the epithelial immune activation in response to C. albicans differs not only between mucosal and parenchymal cells, it is also cell type-specific. Moreover, the cytokine secretion can be modulated by alterations in the fungal cell wall in the absence of Mnn9.



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