Inhibition of Classical and Alternative Modes of Respiration in <italic toggle="yes">Candida albicans</italic> Leads to Cell Wall Remodeling and Increased Macrophage Recognition

ABSTRACT The human fungal pathogen Candida albicans requires respiratory function for normal growth, morphogenesis, and virulence. Mitochondria therefore represent an enticing target for the development of new antifungal strategies. This possibility is bolstered by the presence of characteristics sp...

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Autores principales:	Lucian Duvenage, Louise A. Walker, Aleksandra Bojarczuk, Simon A. Johnston, Donna M. MacCallum, Carol A. Munro, Campbell W. Gourlay
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Candida albicans cell wall mitochondria mycology yeast Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d09b6a0106be494e92b07724b0b9b1ca
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spelling	oai:doaj.org-article:d09b6a0106be494e92b07724b0b9b1ca2021-11-15T15:55:14ZInhibition of Classical and Alternative Modes of Respiration in <italic toggle="yes">Candida albicans</italic> Leads to Cell Wall Remodeling and Increased Macrophage Recognition10.1128/mBio.02535-182150-7511https://doaj.org/article/d09b6a0106be494e92b07724b0b9b1ca2019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02535-18https://doaj.org/toc/2150-7511ABSTRACT The human fungal pathogen Candida albicans requires respiratory function for normal growth, morphogenesis, and virulence. Mitochondria therefore represent an enticing target for the development of new antifungal strategies. This possibility is bolstered by the presence of characteristics specific to fungi. However, respiration in C. albicans, as in many fungal organisms, is facilitated by redundant electron transport mechanisms, making direct inhibition a challenge. In addition, many chemicals known to target the electron transport chain are highly toxic. Here we made use of chemicals with low toxicity to efficiently inhibit respiration in C. albicans. We found that use of the nitric oxide donor sodium nitroprusside (SNP) and of the alternative oxidase inhibitor salicylhydroxamic acid (SHAM) prevents respiration and leads to a loss of viability and to cell wall rearrangements that increase the rate of uptake by macrophages in vitro and in vivo. We propose that treatment with SNP plus SHAM (SNP+SHAM) leads to transcriptional changes that drive cell wall rearrangement but which also prime cells to activate the transition to hyphal growth. In line with this, we found that pretreatment of C. albicans with SNP+SHAM led to an increase in virulence. Our data reveal strong links between respiration, cell wall remodeling, and activation of virulence factors. Our findings demonstrate that respiration in C. albicans can be efficiently inhibited with chemicals that are not damaging to the mammalian host but that we need to develop a deeper understanding of the roles of mitochondria in cellular signaling if they are to be developed successfully as a target for new antifungals. IMPORTANCE Current approaches to tackling fungal infections are limited, and new targets must be identified to protect against the emergence of resistant strains. We investigated the potential of targeting mitochondria, which are organelles required for energy production, growth, and virulence, in the human fungal pathogen Candida albicans. Our findings suggest that mitochondria can be targeted using drugs that can be tolerated by humans and that this treatment enhances their recognition by immune cells. However, release of C. albicans cells from respiratory inhibition appears to activate a stress response that increases the levels of traits associated with virulence. Our results make it clear that mitochondria represent a valid target for the development of antifungal strategies but that we must determine the mechanisms by which they regulate stress signaling and virulence ahead of successful therapeutic advance.Lucian DuvenageLouise A. WalkerAleksandra BojarczukSimon A. JohnstonDonna M. MacCallumCarol A. MunroCampbell W. GourlayAmerican Society for MicrobiologyarticleCandida albicanscell wallmitochondriamycologyyeastMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans cell wall mitochondria mycology yeast Microbiology QR1-502
spellingShingle	Candida albicans cell wall mitochondria mycology yeast Microbiology QR1-502 Lucian Duvenage Louise A. Walker Aleksandra Bojarczuk Simon A. Johnston Donna M. MacCallum Carol A. Munro Campbell W. Gourlay Inhibition of Classical and Alternative Modes of Respiration in <italic toggle="yes">Candida albicans</italic> Leads to Cell Wall Remodeling and Increased Macrophage Recognition
description	ABSTRACT The human fungal pathogen Candida albicans requires respiratory function for normal growth, morphogenesis, and virulence. Mitochondria therefore represent an enticing target for the development of new antifungal strategies. This possibility is bolstered by the presence of characteristics specific to fungi. However, respiration in C. albicans, as in many fungal organisms, is facilitated by redundant electron transport mechanisms, making direct inhibition a challenge. In addition, many chemicals known to target the electron transport chain are highly toxic. Here we made use of chemicals with low toxicity to efficiently inhibit respiration in C. albicans. We found that use of the nitric oxide donor sodium nitroprusside (SNP) and of the alternative oxidase inhibitor salicylhydroxamic acid (SHAM) prevents respiration and leads to a loss of viability and to cell wall rearrangements that increase the rate of uptake by macrophages in vitro and in vivo. We propose that treatment with SNP plus SHAM (SNP+SHAM) leads to transcriptional changes that drive cell wall rearrangement but which also prime cells to activate the transition to hyphal growth. In line with this, we found that pretreatment of C. albicans with SNP+SHAM led to an increase in virulence. Our data reveal strong links between respiration, cell wall remodeling, and activation of virulence factors. Our findings demonstrate that respiration in C. albicans can be efficiently inhibited with chemicals that are not damaging to the mammalian host but that we need to develop a deeper understanding of the roles of mitochondria in cellular signaling if they are to be developed successfully as a target for new antifungals. IMPORTANCE Current approaches to tackling fungal infections are limited, and new targets must be identified to protect against the emergence of resistant strains. We investigated the potential of targeting mitochondria, which are organelles required for energy production, growth, and virulence, in the human fungal pathogen Candida albicans. Our findings suggest that mitochondria can be targeted using drugs that can be tolerated by humans and that this treatment enhances their recognition by immune cells. However, release of C. albicans cells from respiratory inhibition appears to activate a stress response that increases the levels of traits associated with virulence. Our results make it clear that mitochondria represent a valid target for the development of antifungal strategies but that we must determine the mechanisms by which they regulate stress signaling and virulence ahead of successful therapeutic advance.
format	article
author	Lucian Duvenage Louise A. Walker Aleksandra Bojarczuk Simon A. Johnston Donna M. MacCallum Carol A. Munro Campbell W. Gourlay
author_facet	Lucian Duvenage Louise A. Walker Aleksandra Bojarczuk Simon A. Johnston Donna M. MacCallum Carol A. Munro Campbell W. Gourlay
author_sort	Lucian Duvenage
title	Inhibition of Classical and Alternative Modes of Respiration in <italic toggle="yes">Candida albicans</italic> Leads to Cell Wall Remodeling and Increased Macrophage Recognition
title_short	Inhibition of Classical and Alternative Modes of Respiration in <italic toggle="yes">Candida albicans</italic> Leads to Cell Wall Remodeling and Increased Macrophage Recognition
title_full	Inhibition of Classical and Alternative Modes of Respiration in <italic toggle="yes">Candida albicans</italic> Leads to Cell Wall Remodeling and Increased Macrophage Recognition
title_fullStr	Inhibition of Classical and Alternative Modes of Respiration in <italic toggle="yes">Candida albicans</italic> Leads to Cell Wall Remodeling and Increased Macrophage Recognition
title_full_unstemmed	Inhibition of Classical and Alternative Modes of Respiration in <italic toggle="yes">Candida albicans</italic> Leads to Cell Wall Remodeling and Increased Macrophage Recognition
title_sort	inhibition of classical and alternative modes of respiration in <italic toggle="yes">candida albicans</italic> leads to cell wall remodeling and increased macrophage recognition
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/d09b6a0106be494e92b07724b0b9b1ca
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Inhibition of Classical and Alternative Modes of Respiration in <italic toggle="yes">Candida albicans</italic> Leads to Cell Wall Remodeling and Increased Macrophage Recognition

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