Multiple Alternative Carbon Pathways Combine To Promote <named-content content-type="genus-species">Candida albicans</named-content> Stress Resistance, Immune Interactions, and Virulence

ABSTRACT The phagocytic cells of the innate immune system are an essential first line of antimicrobial defense, and yet Candida albicans, one of the most problematic fungal pathogens, is capable of resisting the stresses imposed by the macrophage phagosome, eventually resulting in the destruction of...

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Autores principales:	Robert B. Williams, Michael C. Lorenz
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Candida macrophage virulence carboxylic acid amino acid N-acetylglucosamine Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d0b96f2fdd0249c9a956d4b97c2b352e
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spelling	oai:doaj.org-article:d0b96f2fdd0249c9a956d4b97c2b352e2021-11-15T15:56:58ZMultiple Alternative Carbon Pathways Combine To Promote <named-content content-type="genus-species">Candida albicans</named-content> Stress Resistance, Immune Interactions, and Virulence10.1128/mBio.03070-192150-7511https://doaj.org/article/d0b96f2fdd0249c9a956d4b97c2b352e2020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03070-19https://doaj.org/toc/2150-7511ABSTRACT The phagocytic cells of the innate immune system are an essential first line of antimicrobial defense, and yet Candida albicans, one of the most problematic fungal pathogens, is capable of resisting the stresses imposed by the macrophage phagosome, eventually resulting in the destruction of the phagocyte. C. albicans rapidly adapts to the phagosome by upregulating multiple alternative carbon utilization pathways, particularly those for amino acids, carboxylic acids, and N-acetylglucosamine (GlcNAc). Here, we report that C. albicans recognizes these carbon sources both as crucial nutrients and as independent signals in its environment. Even in the presence of glucose, each carbon source promotes increased resistance to a unique profile of stressors; lactate promotes increased resistance to osmotic and cell wall stresses, amino acids increased resistance to oxidative and nitrosative stresses, and GlcNAc increased resistance to oxidative stress and caspofungin, while all three alternative carbon sources have been shown to induce resistance to fluconazole. Moreover, we show mutants incapable of utilizing these carbon sources, in particular, strains engineered to be defective in all three pathways, are significantly attenuated in both macrophage and mouse models, with additive effects observed as multiple carbon pathways are eliminated, suggesting that C. albicans simultaneously utilizes multiple carbon sources within the macrophage phagosome and during disseminated candidiasis. Taking the data together, we propose that, in addition to providing energy to the pathogen within host environments, alternative carbon sources serve as niche-specific priming signals that allow C. albicans to recognize microenvironments within the host and to prepare for stresses associated with that niche, thus promoting host adaptation and virulence. IMPORTANCE Candida albicans is a fungal pathogen and a significant cause of morbidity and mortality, particularly in people with defects, sometimes minor ones, in innate immunity. The phagocytes of the innate immune system, particularly macrophages and neutrophils, generally restrict this organism to its normal commensal niches, but C. albicans shows a robust and multifaceted response to these cell types. Inside macrophages, a key component of this response is the activation of multiple pathways for the utilization of alternative carbon sources, particularly amino acids, carboxylic acids, and N-acetylglucosamine. These carbon sources are key sources of energy and biomass but also independently promote stress resistance, induce cell wall alterations, and affect C. albicans interactions with macrophages. Engineered strains incapable of utilizing these alternative carbon pathways are attenuated in infection models. These data suggest that C. albicans recognizes nutrient composition as an indicator of specific host environments and tailors its responses accordingly.Robert B. WilliamsMichael C. LorenzAmerican Society for MicrobiologyarticleCandidamacrophagevirulencecarboxylic acidamino acidN-acetylglucosamineMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida macrophage virulence carboxylic acid amino acid N-acetylglucosamine Microbiology QR1-502
spellingShingle	Candida macrophage virulence carboxylic acid amino acid N-acetylglucosamine Microbiology QR1-502 Robert B. Williams Michael C. Lorenz Multiple Alternative Carbon Pathways Combine To Promote <named-content content-type="genus-species">Candida albicans</named-content> Stress Resistance, Immune Interactions, and Virulence
description	ABSTRACT The phagocytic cells of the innate immune system are an essential first line of antimicrobial defense, and yet Candida albicans, one of the most problematic fungal pathogens, is capable of resisting the stresses imposed by the macrophage phagosome, eventually resulting in the destruction of the phagocyte. C. albicans rapidly adapts to the phagosome by upregulating multiple alternative carbon utilization pathways, particularly those for amino acids, carboxylic acids, and N-acetylglucosamine (GlcNAc). Here, we report that C. albicans recognizes these carbon sources both as crucial nutrients and as independent signals in its environment. Even in the presence of glucose, each carbon source promotes increased resistance to a unique profile of stressors; lactate promotes increased resistance to osmotic and cell wall stresses, amino acids increased resistance to oxidative and nitrosative stresses, and GlcNAc increased resistance to oxidative stress and caspofungin, while all three alternative carbon sources have been shown to induce resistance to fluconazole. Moreover, we show mutants incapable of utilizing these carbon sources, in particular, strains engineered to be defective in all three pathways, are significantly attenuated in both macrophage and mouse models, with additive effects observed as multiple carbon pathways are eliminated, suggesting that C. albicans simultaneously utilizes multiple carbon sources within the macrophage phagosome and during disseminated candidiasis. Taking the data together, we propose that, in addition to providing energy to the pathogen within host environments, alternative carbon sources serve as niche-specific priming signals that allow C. albicans to recognize microenvironments within the host and to prepare for stresses associated with that niche, thus promoting host adaptation and virulence. IMPORTANCE Candida albicans is a fungal pathogen and a significant cause of morbidity and mortality, particularly in people with defects, sometimes minor ones, in innate immunity. The phagocytes of the innate immune system, particularly macrophages and neutrophils, generally restrict this organism to its normal commensal niches, but C. albicans shows a robust and multifaceted response to these cell types. Inside macrophages, a key component of this response is the activation of multiple pathways for the utilization of alternative carbon sources, particularly amino acids, carboxylic acids, and N-acetylglucosamine. These carbon sources are key sources of energy and biomass but also independently promote stress resistance, induce cell wall alterations, and affect C. albicans interactions with macrophages. Engineered strains incapable of utilizing these alternative carbon pathways are attenuated in infection models. These data suggest that C. albicans recognizes nutrient composition as an indicator of specific host environments and tailors its responses accordingly.
format	article
author	Robert B. Williams Michael C. Lorenz
author_facet	Robert B. Williams Michael C. Lorenz
author_sort	Robert B. Williams
title	Multiple Alternative Carbon Pathways Combine To Promote <named-content content-type="genus-species">Candida albicans</named-content> Stress Resistance, Immune Interactions, and Virulence
title_short	Multiple Alternative Carbon Pathways Combine To Promote <named-content content-type="genus-species">Candida albicans</named-content> Stress Resistance, Immune Interactions, and Virulence
title_full	Multiple Alternative Carbon Pathways Combine To Promote <named-content content-type="genus-species">Candida albicans</named-content> Stress Resistance, Immune Interactions, and Virulence
title_fullStr	Multiple Alternative Carbon Pathways Combine To Promote <named-content content-type="genus-species">Candida albicans</named-content> Stress Resistance, Immune Interactions, and Virulence
title_full_unstemmed	Multiple Alternative Carbon Pathways Combine To Promote <named-content content-type="genus-species">Candida albicans</named-content> Stress Resistance, Immune Interactions, and Virulence
title_sort	multiple alternative carbon pathways combine to promote <named-content content-type="genus-species">candida albicans</named-content> stress resistance, immune interactions, and virulence
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/d0b96f2fdd0249c9a956d4b97c2b352e
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Multiple Alternative Carbon Pathways Combine To Promote <named-content content-type="genus-species">Candida albicans</named-content> Stress Resistance, Immune Interactions, and Virulence

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