title: Mnn10 Maintains Pathogenicity in Candida albicans by Extending α-1,6-Mannose Backbone to Evade Host Dectin-1 Mediated Antifungal Immunity.
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.
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, PR China.
authors.forename: Shi Qun
authors.initials: SQ
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai, PR China.
authors.forename: Zui
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Dermatology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, PR China.
authors.forename: Shuai Shuai
authors.initials: SS
authors.lastname: Shen
authors.affiliation: Department of Laboratory Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai, PR China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Miao
authors.affiliation: Department of Dermatology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, PR China.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, PR China.
authors.forename: Li Ping
authors.initials: LP
authors.lastname: Li
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, PR China.
authors.forename: Si Min
authors.initials: SM
authors.lastname: Chen
authors.affiliation: R&D Center of New Drug, School of Pharmacy, Second Military Medical University, Shanghai, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yan
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, PR China.
authors.forename: Jun Dong
authors.initials: JD
authors.lastname: Zhang
authors.affiliation: Department of Dermatology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, PR China.
authors.forename: Jing Jun
authors.initials: JJ
authors.lastname: Zhao
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, PR China.
authors.forename: Guo Tong
authors.initials: GT
authors.lastname: Xu
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, PR China.
authors.forename: Mao Mao
authors.initials: MM
authors.lastname: An
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, PR China.|R&D Center of New Drug, School of Pharmacy, Second Military Medical University, Shanghai, PR China.
authors.forename: Yuan Ying
authors.initials: YY
authors.lastname: Jiang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002176:Candida albicans / Q000276:immunology / Q000472:pathogenicity*; D002177:Candidiasis / Q000276:immunology*; D002460:Cell Line; D002473:Cell Wall / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005656:Fungal Proteins / Q000276:immunology / Q000378:metabolism; D006801:Humans; D057131:Immune Evasion / Q000276:immunology*; D037181:Lectins, C-Type / Q000276:immunology*; D008351:Mannans / Q000276:immunology / Q000378:metabolism; D008358:Mannose / Q000378:metabolism; D008364:Mannosyltransferases / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D014774:Virulence / Q000276:immunology*; D000099181:Dectin-1
chemical_list: D005656:Fungal Proteins; D037181:Lectins, C-Type; D008351:Mannans; D008358:Mannose; D008364:Mannosyltransferases; D000099181:Dectin-1