Research Article: Mnn10 Maintains Pathogenicity in Candida albicans by Extending α-1,6-Mannose Backbone to Evade Host Dectin-1 Mediated Antifungal Immunity

Date Published: May 4, 2016

Publisher: Public Library of Science

Author(s): Shi Qun Zhang, Zui Zou, Hui Shen, Shuai Shuai Shen, Qi Miao, Xin Huang, Wei Liu, Li Ping Li, Si Min Chen, Lan Yan, Jun Dong Zhang, Jing Jun Zhao, Guo Tong Xu, Mao Mao An, Yuan Ying Jiang, Robert A. Cramer.


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.

Partial Text

Candida albicans is a common fungal microorganism that colonizes the oral, genital and gastrointestinal surfaces of most healthy individuals. The maintenance of colonization is the result of a complex balance between fungal proliferation and host immune recognition. Despite host immune defenses aimed at clearing pathogens, C. albicans has developed numerous strategies to evade host immune detection [1]. In immunocompromised patients, C. albicans may disseminate into bloodstream, causing life-threatening systemic candidiasis [2, 3]. The associated mortality rates of systemic infection are reported to be greater than 30%, highlighting the potential critical impact of C. albicans on global health burden [4–6].

During C. albicans infection, both yeast cells and hyphae can be found in infected organs or tissues, and innate immune cells discriminate them using different PRRs to elicit a protective immune response [43]. Previous studies have shown that the mannan structure of C. albicans plays an important role in the development of invasive infection. Here we first determined that the cell wall α-1,6-mannose backbone maintained the pathogenicity of C. albicans by preventing host, Dectin-1 mediated, recognition of β-(1,3)-glucan. These results highlight a previously unappreciated relationship between cell wall mannan structure and pathogenicity of C. albicans.




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