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

PLoS Pathogens

Zui Zou¹  Jing Jun Zhao²  Shuai Shuai Shen²  Xin Huang²  Hui Shen³  Qi Miao³  Lan Yan⁴  Guo Tong Xu⁵  Li Ping Li⁵  Yuan Ying Jiang⁵  Mao Mao An⁵  Si Min Chen⁵  Shi Qun Zhang⁵  Jun Dong Zhang⁵  Wei Liu⁵ 

[1] Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai, PR China;Department of Dermatology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, PR China;Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai, PR China;R&D Center of New Drug, School of Pharmacy, Second Military Medical University, Shanghai, PR China;Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, PR China

关键词: C;    ida albicans;    Cell walls;    Macrophages;    Mutant strains;    Neutrophils;    Kidneys;    Cytokines;    Pathogenesis;   

DOI  :  10.1371/journal.ppat.1005617

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY