Epitope Shaving Promotes Fungal Immune Evasion

ABSTRACT The cell wall provides a major physical interface between fungal pathogens and their mammalian host. This extracellular armor is critical for fungal cell homeostasis and survival. Fungus-specific cell wall moieties, such as β-1,3-glucan, are recognized as pathogen-associated molecular patte...

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Autores principales:	Delma S. Childers, Gabriela Mol Avelar, Judith M. Bain, Arnab Pradhan, Daniel E. Larcombe, Mihai G. Netea, Lars P. Erwig, Neil A. R. Gow, Alistair J. P. Brown
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Candida albicans cell wall Xog1 exoglucanase β-glucan shaving immune evasion castanospermine Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4da9c9b4bb334467bcbb87a32cd2e4e6
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spelling	oai:doaj.org-article:4da9c9b4bb334467bcbb87a32cd2e4e62021-11-15T15:56:44ZEpitope Shaving Promotes Fungal Immune Evasion10.1128/mBio.00984-202150-7511https://doaj.org/article/4da9c9b4bb334467bcbb87a32cd2e4e62020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00984-20https://doaj.org/toc/2150-7511ABSTRACT The cell wall provides a major physical interface between fungal pathogens and their mammalian host. This extracellular armor is critical for fungal cell homeostasis and survival. Fungus-specific cell wall moieties, such as β-1,3-glucan, are recognized as pathogen-associated molecular patterns (PAMPs) that activate immune-mediated clearance mechanisms. We have reported that the opportunistic human fungal pathogen Candida albicans masks β-1,3-glucan following exposure to lactate, hypoxia, or iron depletion. However, the precise mechanism(s) by which C. albicans masks β-1,3-glucan has remained obscure. Here, we identify a secreted exoglucanase, Xog1, that is induced in response to lactate or hypoxia. Xog1 functions downstream of the lactate-induced β-glucan “masking” pathway to promote β-1,3-glucan “shaving.” Inactivation of XOG1 blocks most but not all β-1,3-glucan masking in response to lactate, suggesting that other activities contribute to this phenomenon. Nevertheless, XOG1 deletion attenuates the lactate-induced reductions in phagocytosis and cytokine stimulation normally observed for wild-type cells. We also demonstrate that the pharmacological inhibition of exoglucanases undermines β-glucan shaving, enhances the immune visibility of the fungus, and attenuates its virulence. Our study establishes a new mechanism underlying environmentally induced PAMP remodeling that can be manipulated pharmacologically to influence immune recognition and infection outcomes. IMPORTANCE The immune system plays a critical role in protecting us against potentially fatal fungal infections. However, some fungal pathogens have evolved evasion strategies that reduce the efficacy of our immune defenses. Previously, we reported that the fungal pathogen Candida albicans exploits specific host-derived signals (such as lactate and hypoxia) to trigger an immune evasion strategy that involves reducing the exposure of β-glucan at its cell surface. Here, we show that this phenomenon is mediated by the induction of a major secreted exoglucanase (Xog1) by the fungus in response to these host signals. Inactivating XOG1-mediated “shaving” of cell surface-exposed β-glucan enhances immune responses against the fungus. Furthermore, inhibiting exoglucanase activity pharmacologically attenuates C. albicans virulence. In addition to revealing the mechanism underlying a key immune evasion strategy in a major fungal pathogen of humans, our work highlights the potential therapeutic value of drugs that block fungal immune evasion.Delma S. ChildersGabriela Mol AvelarJudith M. BainArnab PradhanDaniel E. LarcombeMihai G. NeteaLars P. ErwigNeil A. R. GowAlistair J. P. BrownAmerican Society for MicrobiologyarticleCandida albicanscell wallXog1 exoglucanaseβ-glucan shavingimmune evasioncastanospermineMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans cell wall Xog1 exoglucanase β-glucan shaving immune evasion castanospermine Microbiology QR1-502
spellingShingle	Candida albicans cell wall Xog1 exoglucanase β-glucan shaving immune evasion castanospermine Microbiology QR1-502 Delma S. Childers Gabriela Mol Avelar Judith M. Bain Arnab Pradhan Daniel E. Larcombe Mihai G. Netea Lars P. Erwig Neil A. R. Gow Alistair J. P. Brown Epitope Shaving Promotes Fungal Immune Evasion
description	ABSTRACT The cell wall provides a major physical interface between fungal pathogens and their mammalian host. This extracellular armor is critical for fungal cell homeostasis and survival. Fungus-specific cell wall moieties, such as β-1,3-glucan, are recognized as pathogen-associated molecular patterns (PAMPs) that activate immune-mediated clearance mechanisms. We have reported that the opportunistic human fungal pathogen Candida albicans masks β-1,3-glucan following exposure to lactate, hypoxia, or iron depletion. However, the precise mechanism(s) by which C. albicans masks β-1,3-glucan has remained obscure. Here, we identify a secreted exoglucanase, Xog1, that is induced in response to lactate or hypoxia. Xog1 functions downstream of the lactate-induced β-glucan “masking” pathway to promote β-1,3-glucan “shaving.” Inactivation of XOG1 blocks most but not all β-1,3-glucan masking in response to lactate, suggesting that other activities contribute to this phenomenon. Nevertheless, XOG1 deletion attenuates the lactate-induced reductions in phagocytosis and cytokine stimulation normally observed for wild-type cells. We also demonstrate that the pharmacological inhibition of exoglucanases undermines β-glucan shaving, enhances the immune visibility of the fungus, and attenuates its virulence. Our study establishes a new mechanism underlying environmentally induced PAMP remodeling that can be manipulated pharmacologically to influence immune recognition and infection outcomes. IMPORTANCE The immune system plays a critical role in protecting us against potentially fatal fungal infections. However, some fungal pathogens have evolved evasion strategies that reduce the efficacy of our immune defenses. Previously, we reported that the fungal pathogen Candida albicans exploits specific host-derived signals (such as lactate and hypoxia) to trigger an immune evasion strategy that involves reducing the exposure of β-glucan at its cell surface. Here, we show that this phenomenon is mediated by the induction of a major secreted exoglucanase (Xog1) by the fungus in response to these host signals. Inactivating XOG1-mediated “shaving” of cell surface-exposed β-glucan enhances immune responses against the fungus. Furthermore, inhibiting exoglucanase activity pharmacologically attenuates C. albicans virulence. In addition to revealing the mechanism underlying a key immune evasion strategy in a major fungal pathogen of humans, our work highlights the potential therapeutic value of drugs that block fungal immune evasion.
format	article
author	Delma S. Childers Gabriela Mol Avelar Judith M. Bain Arnab Pradhan Daniel E. Larcombe Mihai G. Netea Lars P. Erwig Neil A. R. Gow Alistair J. P. Brown
author_facet	Delma S. Childers Gabriela Mol Avelar Judith M. Bain Arnab Pradhan Daniel E. Larcombe Mihai G. Netea Lars P. Erwig Neil A. R. Gow Alistair J. P. Brown
author_sort	Delma S. Childers
title	Epitope Shaving Promotes Fungal Immune Evasion
title_short	Epitope Shaving Promotes Fungal Immune Evasion
title_full	Epitope Shaving Promotes Fungal Immune Evasion
title_fullStr	Epitope Shaving Promotes Fungal Immune Evasion
title_full_unstemmed	Epitope Shaving Promotes Fungal Immune Evasion
title_sort	epitope shaving promotes fungal immune evasion
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/4da9c9b4bb334467bcbb87a32cd2e4e6
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Epitope Shaving Promotes Fungal Immune Evasion

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