Abstract
The cell wall is a dynamic structure that is important for the pathogenicity of Candida albicans. Mannan, which is located in the outermost layer of the cell wall, has been shown to contribute to the pathogenesis of C. albicans, however, the molecular mechanism by which this occurs remains unclear. Here we identified a novel α-1,6-mannosyltransferase encoded by MNN10 in C. albicans. We found that Mnn10 is required for cell wall α-1,6-mannose backbone biosynthesis and polysaccharides organization. Deletion of MNN10 resulted in significant attenuation of the pathogenesis of C. albicans in a murine systemic candidiasis model. Inhibition of α-1,6-mannose backbone extension did not, however, impact the invasive ability of C. albicans in vitro. Notably, mnn10 mutant restored the invasive capacity in athymic nude mice, which further supports the notion of an enhanced host antifungal defense related to this backbone change. Mnn10 mutant induced enhanced Th1 and Th17 cell mediated antifungal immunity, and resulted in enhanced recruitment of neutrophils and monocytes for pathogen clearance in vivo. We also demonstrated that MNN10 could unmask the surface β-(1,3)-glucan, a crucial pathogen-associated molecular pattern (PAMP) of C. albicans recognized by host Dectin-1. Our results demonstrate that mnn10 mutant could stimulate an enhanced Dectin-1 dependent immune response of macrophages in vitro, including the activation of nuclear factor-κB, mitogen-activated protein kinase pathways, and secretion of specific cytokines such as TNF-α, IL-6, IL-1β and IL-12p40. In summary, our study indicated that α-1,6-mannose backbone is critical for the pathogenesis of C. albicans via shielding β-glucan from recognition by host Dectin-1 mediated immune recognition. Moreover, our work suggests that inhibition of α-1,6-mannose extension by Mnn10 may represent a novel modality to reduce the pathogenicity of C. albicans.
Highlights
Candida albicans is a common fungal microorganism that colonizes the oral, genital and gastrointestinal surfaces of most healthy individuals
Mannan plays a crucial role in cell wall structure and virulence of the opportunistic pathogen Candida albicans
We identified a novel α-1,6-mannosyltransferase, which was responsible for cell wall α-1,6mannose backbone extension in C. albicans
Summary
Candida albicans is a common fungal microorganism that colonizes the oral, genital and gastrointestinal surfaces of most healthy individuals. The mature cell wall of C. albicans is a complex structure of cross-linked polysaccharides and glycosylated proteins. N-linked mannan chains are required for cell morphology, phagocytosis, and immune recognition of C. albicans by host dendritic cells [8]. The α-1,6-backbone is further modified with additional α-1,2-mannose units by Mnn family and Mnn, which are critical for C. albicans virulence in mice or Galleria mellonella [11, 12]. Bmt and Bmt, which are required for the addition of the first and second β-1,2-mannose units respectively, are not associated with the virulence of C. albicans [14]. A variety of C. albicans mannosylation mutants have been found to be less pathogenic in vivo, the mechanisms of host clearance associated with abnormal mannan structures remains unclear
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