title: Abolishing Cell Wall Glycosylphosphatidylinositol-Anchored Proteins in Candida albicans Enhances Recognition by Host Dectin-1.
abstract: Fungi can shield surface pathogen-associated molecular patterns (PAMPs) for evading host immune attack. The most common and opportunistic human pathogen, Candida albicans, can shield β-(1 3)-glucan on the cell wall, one of the major PAMPs, to avoid host phagocyte Dectin-1 recognition. The way to interfere in the shielding process for more effective antifungal defense is not well established. In this study, we found that deletion of the C. albicans GPI7 gene, which was responsible for adding ethanolaminephosphate to the second mannose in glycosylphosphatidylinositol (GPI) biosynthesis, could block the attachment of most GPI-anchored cell wall proteins (GPI-CWPs) to the cell wall and subsequently unmask the concealed β-(1,3)-glucan. Neutrophils could kill the uncloaked gpi7 mutant more efficiently with an augmented respiratory burst. The gpi7 mutant also stimulated Dectin-1-dependent immune responses of macrophages, including activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways and secretion of specific cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and IL-12p40. Furthermore, the gpi7 null mutant could induce an enhanced inflammatory response through promoting significant recruitment of neutrophils and monocytes and could stimulate stronger Th1 and Th17 cell responses to fungal infections in vivo. These in vivo phenotypes also were Dectin-1 dependent. Thus, we assume that GPI-CWPs are involved in the immune mechanism of C. albicans escaping from host recognition by Dectin-1. Our studies also indicate that the blockage of GPI anchor synthesis is a strategy to inhibit C. albicans evading host recognition.
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Si Min
authors.initials: SM
authors.lastname: Chen
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, People's Republic of 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, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhu
authors.affiliation: R&D Center of New Drug, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Li Juan
authors.initials: LJ
authors.lastname: He
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Jun Dong
authors.initials: JD
authors.lastname: Zhang
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Shi Qun
authors.initials: SQ
authors.lastname: Zhang
authors.affiliation: R&D Center of New Drug, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yan
authors.affiliation: R&D Center of New Drug, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Shanghai Tenth People's Hospital, and Department of Pharmacology, Tongji University School of Medicine, Shanghai, People's Republic of 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, People's Republic of China anmaomao@tongji.edu.cn jiangyy@tongji.edu.cn.
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, People's Republic of China R&D Center of New Drug, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China anmaomao@tongji.edu.cn jiangyy@tongji.edu.cn.
authors.forename: Yuan Ying
authors.initials: YY
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology* / Q000378:metabolism; D002176:Candida albicans / Q000276:immunology* / Q000378:metabolism; D002473:Cell Wall / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005656:Fungal Proteins / Q000276:immunology* / Q000378:metabolism; D017353:Gene Deletion; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D037181:Lectins, C-Type / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D047071:beta-Glucans / Q000276:immunology / Q000378:metabolism; D000099181:Dectin-1
chemical_list: D000946:Antigens, Fungal; D005656:Fungal Proteins; D017261:Glycosylphosphatidylinositols; D037181:Lectins, C-Type; D017853:Phosphotransferases (Alcohol Group Acceptor); D047071:beta-Glucans; D000099181:Dectin-1; C033363:beta-1,3-glucan