Inhibition of classical and alternative modes of respiration in Candida albicans leads to cell wall remodelling and increased macrophage recognition

Lucian Duvenage, Louise A. Walker, Aleksandra Bojarczuk, Simon A. Johnston, Donna M. MacCallum, Carol A. Munro (Corresponding Author), Campbell W. Gourlay (Corresponding Author)

Research output: Contribution to journalArticle

3 Citations (Scopus)
5 Downloads (Pure)

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.

Original languageEnglish
Article numbere02535-18
JournalmBio
Volume10
Issue number1
Early online date29 Jan 2019
DOIs
Publication statusPublished - 29 Jan 2019

Fingerprint

Candida albicans
Cell Wall
Respiration
Macrophages
Virulence
Nitroprusside
Mitochondria
Electron Transport
Growth
Nitric Oxide Donors
Mycoses
Poisons
Virulence Factors
Morphogenesis
Organelles
Fungi
salicylhydroxamic acid
Pharmaceutical Preparations

Keywords

  • Candida albicans
  • cell wall
  • mitochondria
  • mycology
  • yeast
  • Candidiasis/microbiology
  • Cell Line
  • Candida albicans/drug effects
  • Zebrafish
  • Cell Survival/drug effects
  • Macrophages/immunology
  • Oxygen/metabolism
  • Nitroprusside/metabolism
  • Animals
  • Electron Transport/drug effects
  • Mice
  • Virulence/drug effects
  • Kidney/pathology
  • Cell Wall/drug effects
  • Salicylamides/metabolism
  • MITOCHONDRIA
  • HYPOXIC RESPONSE
  • INTEGRITY
  • NITRIC-OXIDE
  • OXIDATIVE STRESS
  • IMMUNE RECOGNITION
  • ERGOSTEROL LEVELS
  • GENE
  • COMPLEX-I
  • RESISTANCE

ASJC Scopus subject areas

  • Virology
  • Microbiology

Cite this

Inhibition of classical and alternative modes of respiration in Candida albicans leads to cell wall remodelling and increased macrophage recognition. / Duvenage, Lucian; Walker, Louise A.; Bojarczuk, Aleksandra; Johnston, Simon A.; MacCallum, Donna M.; Munro, Carol A. (Corresponding Author); Gourlay, Campbell W. (Corresponding Author).

In: mBio, Vol. 10, No. 1, e02535-18, 29.01.2019.

Research output: Contribution to journalArticle

Duvenage, Lucian ; Walker, Louise A. ; Bojarczuk, Aleksandra ; Johnston, Simon A. ; MacCallum, Donna M. ; Munro, Carol A. ; Gourlay, Campbell W. / Inhibition of classical and alternative modes of respiration in Candida albicans leads to cell wall remodelling and increased macrophage recognition. In: mBio. 2019 ; Vol. 10, No. 1.
@article{05d64f07c91b492c80f213c44bdee4e0,
title = "Inhibition of classical and alternative modes of respiration in Candida albicans leads to cell wall remodelling 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 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.",
keywords = "Candida albicans, cell wall, mitochondria, mycology, yeast, Candidiasis/microbiology, Cell Line, Candida albicans/drug effects, Zebrafish, Cell Survival/drug effects, Macrophages/immunology, Oxygen/metabolism, Nitroprusside/metabolism, Animals, Electron Transport/drug effects, Mice, Virulence/drug effects, Kidney/pathology, Cell Wall/drug effects, Salicylamides/metabolism, MITOCHONDRIA, HYPOXIC RESPONSE, INTEGRITY, NITRIC-OXIDE, OXIDATIVE STRESS, IMMUNE RECOGNITION, ERGOSTEROL LEVELS, GENE, COMPLEX-I, RESISTANCE",
author = "Lucian Duvenage and Walker, {Louise A.} and Aleksandra Bojarczuk and Johnston, {Simon A.} and MacCallum, {Donna M.} and Munro, {Carol A.} and Gourlay, {Campbell W.}",
note = "We thank Professor Gordon Brown (MRC Centre for Medical Mycology, University of Aberdeen) for providing Dectin-1-Fc. We would also thank the Microscopy and Histology Core facility Institute of Medical Sciences, University of Aberdeen where the high pressure freezing was performed and staff at the Centre for Genome Enabled Biology and Medicine (University of Aberdeen Medical Research Facility) who performed RNA sequencing procedures. We would also thank members of both the Aberdeen Fungal Group, Kent Fungal Group and WTSA MMFI consortia for comments and useful discussion throughout the project. CAM and LW acknowledge the support of the Medical Research Council Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1).",
year = "2019",
month = "1",
day = "29",
doi = "10.1128/mBio.02535-18",
language = "English",
volume = "10",
journal = "mBio",
issn = "2161-2129",
publisher = "American Society for Microbiology",
number = "1",

}

TY - JOUR

T1 - Inhibition of classical and alternative modes of respiration in Candida albicans leads to cell wall remodelling and increased macrophage recognition

AU - Duvenage, Lucian

AU - Walker, Louise A.

AU - Bojarczuk, Aleksandra

AU - Johnston, Simon A.

AU - MacCallum, Donna M.

AU - Munro, Carol A.

AU - Gourlay, Campbell W.

N1 - We thank Professor Gordon Brown (MRC Centre for Medical Mycology, University of Aberdeen) for providing Dectin-1-Fc. We would also thank the Microscopy and Histology Core facility Institute of Medical Sciences, University of Aberdeen where the high pressure freezing was performed and staff at the Centre for Genome Enabled Biology and Medicine (University of Aberdeen Medical Research Facility) who performed RNA sequencing procedures. We would also thank members of both the Aberdeen Fungal Group, Kent Fungal Group and WTSA MMFI consortia for comments and useful discussion throughout the project. CAM and LW acknowledge the support of the Medical Research Council Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1).

PY - 2019/1/29

Y1 - 2019/1/29

N2 - 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.

AB - 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.

KW - Candida albicans

KW - cell wall

KW - mitochondria

KW - mycology

KW - yeast

KW - Candidiasis/microbiology

KW - Cell Line

KW - Candida albicans/drug effects

KW - Zebrafish

KW - Cell Survival/drug effects

KW - Macrophages/immunology

KW - Oxygen/metabolism

KW - Nitroprusside/metabolism

KW - Animals

KW - Electron Transport/drug effects

KW - Mice

KW - Virulence/drug effects

KW - Kidney/pathology

KW - Cell Wall/drug effects

KW - Salicylamides/metabolism

KW - MITOCHONDRIA

KW - HYPOXIC RESPONSE

KW - INTEGRITY

KW - NITRIC-OXIDE

KW - OXIDATIVE STRESS

KW - IMMUNE RECOGNITION

KW - ERGOSTEROL LEVELS

KW - GENE

KW - COMPLEX-I

KW - RESISTANCE

UR - http://www.scopus.com/inward/record.url?scp=85060821709&partnerID=8YFLogxK

UR - http://www.mendeley.com/research/inhibition-classical-alternative-modes-respiration-candida-albicans-leads-cell-wall-remodeling-incre

U2 - 10.1128/mBio.02535-18

DO - 10.1128/mBio.02535-18

M3 - Article

C2 - 30696734

AN - SCOPUS:85060821709

VL - 10

JO - mBio

JF - mBio

SN - 2161-2129

IS - 1

M1 - e02535-18

ER -