Mechanisms Underlying the Exquisite Sensitivity of <named-content content-type="genus-species">Candida albicans</named-content> to Combinatorial Cationic and Oxidative Stress That Enhances the Potent Fungicidal Activity of Phagocytes

ABSTRACT Immune cells exploit reactive oxygen species (ROS) and cationic fluxes to kill microbial pathogens, such as the fungus Candida albicans. Yet, C. albicans is resistant to these stresses in vitro. Therefore, what accounts for the potent antifungal activity of neutrophils? We show that simulta...

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Autores principales:	Despoina Kaloriti, Mette Jacobsen, Zhikang Yin, Miranda Patterson, Anna Tillmann, Deborah A. Smith, Emily Cook, Tao You, Melissa J. Grimm, Iryna Bohovych, Celso Grebogi, Brahm H. Segal, Neil A. R. Gow, Ken Haynes, Janet Quinn, Alistair J. P. Brown
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2014
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4dfb09531b17429f9de94c33d6f04296
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spelling	oai:doaj.org-article:4dfb09531b17429f9de94c33d6f042962021-11-15T15:47:22ZMechanisms Underlying the Exquisite Sensitivity of <named-content content-type="genus-species">Candida albicans</named-content> to Combinatorial Cationic and Oxidative Stress That Enhances the Potent Fungicidal Activity of Phagocytes10.1128/mBio.01334-142150-7511https://doaj.org/article/4dfb09531b17429f9de94c33d6f042962014-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01334-14https://doaj.org/toc/2150-7511ABSTRACT Immune cells exploit reactive oxygen species (ROS) and cationic fluxes to kill microbial pathogens, such as the fungus Candida albicans. Yet, C. albicans is resistant to these stresses in vitro. Therefore, what accounts for the potent antifungal activity of neutrophils? We show that simultaneous exposure to oxidative and cationic stresses is much more potent than the individual stresses themselves and that this combinatorial stress kills C. albicans synergistically in vitro. We also show that the high fungicidal activity of human neutrophils is dependent on the combinatorial effects of the oxidative burst and cationic fluxes, as their pharmacological attenuation with apocynin or glibenclamide reduced phagocytic potency to a similar extent. The mechanistic basis for the extreme potency of combinatorial cationic plus oxidative stress—a phenomenon we term stress pathway interference—lies with the inhibition of hydrogen peroxide detoxification by the cations. In C. albicans this causes the intracellular accumulation of ROS, the inhibition of Cap1 (a transcriptional activator that normally drives the transcriptional response to oxidative stress), and altered readouts of the stress-activated protein kinase Hog1. This leads to a loss of oxidative and cationic stress transcriptional outputs, a precipitous collapse in stress adaptation, and cell death. This stress pathway interference can be suppressed by ectopic catalase (Cat1) expression, which inhibits the intracellular accumulation of ROS and the synergistic killing of C. albicans cells by combinatorial cationic plus oxidative stress. Stress pathway interference represents a powerful fungicidal mechanism employed by the host that suggests novel approaches to potentiate antifungal therapy. IMPORTANCE The immune system combats infection via phagocytic cells that recognize and kill pathogenic microbes. Human neutrophils combat Candida infections by killing this fungus with a potent mix of chemicals that includes reactive oxygen species (ROS) and cations. Yet, Candida albicans is relatively resistant to these stresses in vitro. We show that it is the combination of oxidative plus cationic stresses that kills yeasts so effectively, and we define the molecular mechanisms that underlie this potency. Cations inhibit catalase. This leads to the accumulation of intracellular ROS and inhibits the transcription factor Cap1, which is critical for the oxidative stress response in C. albicans. This triggers a dramatic collapse in fungal stress adaptation and cell death. Blocking either the oxidative burst or cationic fluxes in human neutrophils significantly reduces their ability to kill this fungal pathogen, indicating that combinatorial stress is pivotal to immune surveillance.Despoina KaloritiMette JacobsenZhikang YinMiranda PattersonAnna TillmannDeborah A. SmithEmily CookTao YouMelissa J. GrimmIryna BohovychCelso GrebogiBrahm H. SegalNeil A. R. GowKen HaynesJanet QuinnAlistair J. P. BrownAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 5, Iss 4 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Despoina Kaloriti Mette Jacobsen Zhikang Yin Miranda Patterson Anna Tillmann Deborah A. Smith Emily Cook Tao You Melissa J. Grimm Iryna Bohovych Celso Grebogi Brahm H. Segal Neil A. R. Gow Ken Haynes Janet Quinn Alistair J. P. Brown Mechanisms Underlying the Exquisite Sensitivity of <named-content content-type="genus-species">Candida albicans</named-content> to Combinatorial Cationic and Oxidative Stress That Enhances the Potent Fungicidal Activity of Phagocytes
description	ABSTRACT Immune cells exploit reactive oxygen species (ROS) and cationic fluxes to kill microbial pathogens, such as the fungus Candida albicans. Yet, C. albicans is resistant to these stresses in vitro. Therefore, what accounts for the potent antifungal activity of neutrophils? We show that simultaneous exposure to oxidative and cationic stresses is much more potent than the individual stresses themselves and that this combinatorial stress kills C. albicans synergistically in vitro. We also show that the high fungicidal activity of human neutrophils is dependent on the combinatorial effects of the oxidative burst and cationic fluxes, as their pharmacological attenuation with apocynin or glibenclamide reduced phagocytic potency to a similar extent. The mechanistic basis for the extreme potency of combinatorial cationic plus oxidative stress—a phenomenon we term stress pathway interference—lies with the inhibition of hydrogen peroxide detoxification by the cations. In C. albicans this causes the intracellular accumulation of ROS, the inhibition of Cap1 (a transcriptional activator that normally drives the transcriptional response to oxidative stress), and altered readouts of the stress-activated protein kinase Hog1. This leads to a loss of oxidative and cationic stress transcriptional outputs, a precipitous collapse in stress adaptation, and cell death. This stress pathway interference can be suppressed by ectopic catalase (Cat1) expression, which inhibits the intracellular accumulation of ROS and the synergistic killing of C. albicans cells by combinatorial cationic plus oxidative stress. Stress pathway interference represents a powerful fungicidal mechanism employed by the host that suggests novel approaches to potentiate antifungal therapy. IMPORTANCE The immune system combats infection via phagocytic cells that recognize and kill pathogenic microbes. Human neutrophils combat Candida infections by killing this fungus with a potent mix of chemicals that includes reactive oxygen species (ROS) and cations. Yet, Candida albicans is relatively resistant to these stresses in vitro. We show that it is the combination of oxidative plus cationic stresses that kills yeasts so effectively, and we define the molecular mechanisms that underlie this potency. Cations inhibit catalase. This leads to the accumulation of intracellular ROS and inhibits the transcription factor Cap1, which is critical for the oxidative stress response in C. albicans. This triggers a dramatic collapse in fungal stress adaptation and cell death. Blocking either the oxidative burst or cationic fluxes in human neutrophils significantly reduces their ability to kill this fungal pathogen, indicating that combinatorial stress is pivotal to immune surveillance.
format	article
author	Despoina Kaloriti Mette Jacobsen Zhikang Yin Miranda Patterson Anna Tillmann Deborah A. Smith Emily Cook Tao You Melissa J. Grimm Iryna Bohovych Celso Grebogi Brahm H. Segal Neil A. R. Gow Ken Haynes Janet Quinn Alistair J. P. Brown
author_facet	Despoina Kaloriti Mette Jacobsen Zhikang Yin Miranda Patterson Anna Tillmann Deborah A. Smith Emily Cook Tao You Melissa J. Grimm Iryna Bohovych Celso Grebogi Brahm H. Segal Neil A. R. Gow Ken Haynes Janet Quinn Alistair J. P. Brown
author_sort	Despoina Kaloriti
title	Mechanisms Underlying the Exquisite Sensitivity of <named-content content-type="genus-species">Candida albicans</named-content> to Combinatorial Cationic and Oxidative Stress That Enhances the Potent Fungicidal Activity of Phagocytes
title_short	Mechanisms Underlying the Exquisite Sensitivity of <named-content content-type="genus-species">Candida albicans</named-content> to Combinatorial Cationic and Oxidative Stress That Enhances the Potent Fungicidal Activity of Phagocytes
title_full	Mechanisms Underlying the Exquisite Sensitivity of <named-content content-type="genus-species">Candida albicans</named-content> to Combinatorial Cationic and Oxidative Stress That Enhances the Potent Fungicidal Activity of Phagocytes
title_fullStr	Mechanisms Underlying the Exquisite Sensitivity of <named-content content-type="genus-species">Candida albicans</named-content> to Combinatorial Cationic and Oxidative Stress That Enhances the Potent Fungicidal Activity of Phagocytes
title_full_unstemmed	Mechanisms Underlying the Exquisite Sensitivity of <named-content content-type="genus-species">Candida albicans</named-content> to Combinatorial Cationic and Oxidative Stress That Enhances the Potent Fungicidal Activity of Phagocytes
title_sort	mechanisms underlying the exquisite sensitivity of <named-content content-type="genus-species">candida albicans</named-content> to combinatorial cationic and oxidative stress that enhances the potent fungicidal activity of phagocytes
publisher	American Society for Microbiology
publishDate	2014
url	https://doaj.org/article/4dfb09531b17429f9de94c33d6f04296
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Mechanisms Underlying the Exquisite Sensitivity of <named-content content-type="genus-species">Candida albicans</named-content> to Combinatorial Cationic and Oxidative Stress That Enhances the Potent Fungicidal Activity of Phagocytes

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