Inhibition of Respiration of <named-content content-type="genus-species">Candida albicans</named-content> by Small Molecules Increases Phagocytosis Efficacy by Macrophages

ABSTRACT Candida albicans adapts to various conditions in different body niches by regulating gene expression, protein synthesis, and metabolic pathways. These adaptive reactions not only allow survival but also influence the interaction with host cells, which is governed by the composition and stru...

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Autores principales: Shuna Cui, Minghui Li, Rabeay Y. A. Hassan, Anna Heintz-Buschart, Junsong Wang, Ursula Bilitewski
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Publicado: American Society for Microbiology 2020
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spelling oai:doaj.org-article:95247721310b45e9b5e987502dccc17b2021-11-15T15:29:16ZInhibition of Respiration of <named-content content-type="genus-species">Candida albicans</named-content> by Small Molecules Increases Phagocytosis Efficacy by Macrophages10.1128/mSphere.00016-202379-5042https://doaj.org/article/95247721310b45e9b5e987502dccc17b2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00016-20https://doaj.org/toc/2379-5042ABSTRACT Candida albicans adapts to various conditions in different body niches by regulating gene expression, protein synthesis, and metabolic pathways. These adaptive reactions not only allow survival but also influence the interaction with host cells, which is governed by the composition and structure of the fungal cell wall. Numerous studies had shown linkages between mitochondrial functionality, cell wall integrity and structure, and pathogenicity. Thus, we decided to inhibit single complexes of the respiratory chain of C. albicans and to analyze the resultant interaction with macrophages via their phagocytic activity. Remarkably, inhibition of the fungal bc1 complex by antimycin A increased phagocytosis, which correlated with an increased accessibility of β-glucans. To contribute to mechanistic insights, we performed metabolic studies, which highlighted significant changes in the abundance of constituents of the plasma membrane. Collectively, our results reinforce the strong linkage between fungal energy metabolism and other components of fungal physiology, which also determine the vulnerability to immune defense reactions. IMPORTANCE The yeast Candida albicans is one of the major fungal human pathogens, for which new therapeutic approaches are required. We aimed at enhancements of the phagocytosis efficacy of macrophages by targeting the cell wall structure of C. albicans, as the coverage of the β-glucan layer by mannans is one of the immune escape mechanisms of the fungus. We unambiguously show that inhibition of the fungal bc1 complex correlates with increased accessibilities of β-glucans and improved phagocytosis efficiency. Metabolic studies proved not only the known direct effects on reactive oxygen species (ROS) production and fermentative pathways but also the clear downregulation of the ergosterol pathway and upregulation of unsaturated fatty acids. The changed composition of the plasma membrane could also influence the interaction with the overlying cell wall. Thus, our work highlights the far-reaching relevance of energy metabolism, indirectly also for host-pathogen interactions, without affecting viability.Shuna CuiMinghui LiRabeay Y. A. HassanAnna Heintz-BuschartJunsong WangUrsula BilitewskiAmerican Society for Microbiologyarticlecomplex IIIrespiratory chainantimycin AphagocytosismetabolismMicrobiologyQR1-502ENmSphere, Vol 5, Iss 2 (2020)
institution DOAJ
collection DOAJ
language EN
topic complex III
respiratory chain
antimycin A
phagocytosis
metabolism
Microbiology
QR1-502
spellingShingle complex III
respiratory chain
antimycin A
phagocytosis
metabolism
Microbiology
QR1-502
Shuna Cui
Minghui Li
Rabeay Y. A. Hassan
Anna Heintz-Buschart
Junsong Wang
Ursula Bilitewski
Inhibition of Respiration of <named-content content-type="genus-species">Candida albicans</named-content> by Small Molecules Increases Phagocytosis Efficacy by Macrophages
description ABSTRACT Candida albicans adapts to various conditions in different body niches by regulating gene expression, protein synthesis, and metabolic pathways. These adaptive reactions not only allow survival but also influence the interaction with host cells, which is governed by the composition and structure of the fungal cell wall. Numerous studies had shown linkages between mitochondrial functionality, cell wall integrity and structure, and pathogenicity. Thus, we decided to inhibit single complexes of the respiratory chain of C. albicans and to analyze the resultant interaction with macrophages via their phagocytic activity. Remarkably, inhibition of the fungal bc1 complex by antimycin A increased phagocytosis, which correlated with an increased accessibility of β-glucans. To contribute to mechanistic insights, we performed metabolic studies, which highlighted significant changes in the abundance of constituents of the plasma membrane. Collectively, our results reinforce the strong linkage between fungal energy metabolism and other components of fungal physiology, which also determine the vulnerability to immune defense reactions. IMPORTANCE The yeast Candida albicans is one of the major fungal human pathogens, for which new therapeutic approaches are required. We aimed at enhancements of the phagocytosis efficacy of macrophages by targeting the cell wall structure of C. albicans, as the coverage of the β-glucan layer by mannans is one of the immune escape mechanisms of the fungus. We unambiguously show that inhibition of the fungal bc1 complex correlates with increased accessibilities of β-glucans and improved phagocytosis efficiency. Metabolic studies proved not only the known direct effects on reactive oxygen species (ROS) production and fermentative pathways but also the clear downregulation of the ergosterol pathway and upregulation of unsaturated fatty acids. The changed composition of the plasma membrane could also influence the interaction with the overlying cell wall. Thus, our work highlights the far-reaching relevance of energy metabolism, indirectly also for host-pathogen interactions, without affecting viability.
format article
author Shuna Cui
Minghui Li
Rabeay Y. A. Hassan
Anna Heintz-Buschart
Junsong Wang
Ursula Bilitewski
author_facet Shuna Cui
Minghui Li
Rabeay Y. A. Hassan
Anna Heintz-Buschart
Junsong Wang
Ursula Bilitewski
author_sort Shuna Cui
title Inhibition of Respiration of <named-content content-type="genus-species">Candida albicans</named-content> by Small Molecules Increases Phagocytosis Efficacy by Macrophages
title_short Inhibition of Respiration of <named-content content-type="genus-species">Candida albicans</named-content> by Small Molecules Increases Phagocytosis Efficacy by Macrophages
title_full Inhibition of Respiration of <named-content content-type="genus-species">Candida albicans</named-content> by Small Molecules Increases Phagocytosis Efficacy by Macrophages
title_fullStr Inhibition of Respiration of <named-content content-type="genus-species">Candida albicans</named-content> by Small Molecules Increases Phagocytosis Efficacy by Macrophages
title_full_unstemmed Inhibition of Respiration of <named-content content-type="genus-species">Candida albicans</named-content> by Small Molecules Increases Phagocytosis Efficacy by Macrophages
title_sort inhibition of respiration of <named-content content-type="genus-species">candida albicans</named-content> by small molecules increases phagocytosis efficacy by macrophages
publisher American Society for Microbiology
publishDate 2020
url https://doaj.org/article/95247721310b45e9b5e987502dccc17b
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