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

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....

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Autores principales: Zhang, Shi Qun, Zou, Zui, Shen, Hui, Shen, Shuai Shuai, Miao, Qi, Huang, Xin, Liu, Wei, Li, Li Ping, Chen, Si Min, Yan, Lan, Zhang, Jun Dong, Zhao, Jing Jun, Xu, Guo Tong, An, Mao Mao, Jiang, Yuan Ying
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856274/
https://www.ncbi.nlm.nih.gov/pubmed/27144456
http://dx.doi.org/10.1371/journal.ppat.1005617
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author Zhang, Shi Qun
Zou, Zui
Shen, Hui
Shen, Shuai Shuai
Miao, Qi
Huang, Xin
Liu, Wei
Li, Li Ping
Chen, Si Min
Yan, Lan
Zhang, Jun Dong
Zhao, Jing Jun
Xu, Guo Tong
An, Mao Mao
Jiang, Yuan Ying
author_facet Zhang, Shi Qun
Zou, Zui
Shen, Hui
Shen, Shuai Shuai
Miao, Qi
Huang, Xin
Liu, Wei
Li, Li Ping
Chen, Si Min
Yan, Lan
Zhang, Jun Dong
Zhao, Jing Jun
Xu, Guo Tong
An, Mao Mao
Jiang, Yuan Ying
author_sort Zhang, Shi Qun
collection PubMed
description 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.
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spelling pubmed-48562742016-05-07 Mnn10 Maintains Pathogenicity in Candida albicans by Extending α-1,6-Mannose Backbone to Evade Host Dectin-1 Mediated Antifungal Immunity Zhang, Shi Qun Zou, Zui Shen, Hui Shen, Shuai Shuai Miao, Qi Huang, Xin Liu, Wei Li, Li Ping Chen, Si Min Yan, Lan Zhang, Jun Dong Zhao, Jing Jun Xu, Guo Tong An, Mao Mao Jiang, Yuan Ying PLoS Pathog Research Article 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. Public Library of Science 2016-05-04 /pmc/articles/PMC4856274/ /pubmed/27144456 http://dx.doi.org/10.1371/journal.ppat.1005617 Text en © 2016 Zhang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Zhang, Shi Qun
Zou, Zui
Shen, Hui
Shen, Shuai Shuai
Miao, Qi
Huang, Xin
Liu, Wei
Li, Li Ping
Chen, Si Min
Yan, Lan
Zhang, Jun Dong
Zhao, Jing Jun
Xu, Guo Tong
An, Mao Mao
Jiang, Yuan Ying
Mnn10 Maintains Pathogenicity in Candida albicans by Extending α-1,6-Mannose Backbone to Evade Host Dectin-1 Mediated Antifungal Immunity
title Mnn10 Maintains Pathogenicity in Candida albicans by Extending α-1,6-Mannose Backbone to Evade Host Dectin-1 Mediated Antifungal Immunity
title_full Mnn10 Maintains Pathogenicity in Candida albicans by Extending α-1,6-Mannose Backbone to Evade Host Dectin-1 Mediated Antifungal Immunity
title_fullStr Mnn10 Maintains Pathogenicity in Candida albicans by Extending α-1,6-Mannose Backbone to Evade Host Dectin-1 Mediated Antifungal Immunity
title_full_unstemmed Mnn10 Maintains Pathogenicity in Candida albicans by Extending α-1,6-Mannose Backbone to Evade Host Dectin-1 Mediated Antifungal Immunity
title_short Mnn10 Maintains Pathogenicity in Candida albicans by Extending α-1,6-Mannose Backbone to Evade Host Dectin-1 Mediated Antifungal Immunity
title_sort mnn10 maintains pathogenicity in candida albicans by extending α-1,6-mannose backbone to evade host dectin-1 mediated antifungal immunity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4856274/
https://www.ncbi.nlm.nih.gov/pubmed/27144456
http://dx.doi.org/10.1371/journal.ppat.1005617
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