The Two-Component Response Regulator Ssk1 and the Mitogen-Activated Protein Kinase Hog1 Control Antifungal Drug Resistance and Cell Wall Architecture of <named-content content-type="genus-species">Candida auris</named-content>

ABSTRACT Candida auris is an emerging multidrug-resistant human fungal pathogen refractory to treatment by several classes of antifungal drugs. Unlike other Candida species, C. auris can adhere to human skin for prolonged periods of time, allowing for efficient skin-to-skin transmission in the hospi...

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Autores principales:	Raju Shivarathri, Sabrina Jenull, Anton Stoiber, Manju Chauhan, Rounik Mazumdar, Ashutosh Singh, Filomena Nogueira, Karl Kuchler, Anuradha Chowdhary, Neeraj Chauhan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Candida auris SSK1 HOG1 multidrug resistance cell wall MAPK signaling Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/9895c8d7992a4d8dab734dccd07fb996
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spelling	oai:doaj.org-article:9895c8d7992a4d8dab734dccd07fb9962021-11-15T15:30:58ZThe Two-Component Response Regulator Ssk1 and the Mitogen-Activated Protein Kinase Hog1 Control Antifungal Drug Resistance and Cell Wall Architecture of <named-content content-type="genus-species">Candida auris</named-content>10.1128/mSphere.00973-202379-5042https://doaj.org/article/9895c8d7992a4d8dab734dccd07fb9962020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00973-20https://doaj.org/toc/2379-5042ABSTRACT Candida auris is an emerging multidrug-resistant human fungal pathogen refractory to treatment by several classes of antifungal drugs. Unlike other Candida species, C. auris can adhere to human skin for prolonged periods of time, allowing for efficient skin-to-skin transmission in the hospital environments. However, molecular mechanisms underlying pronounced multidrug resistance and adhesion traits are poorly understood. Two-component signal transduction and mitogen-activated protein (MAP) kinase signaling are important regulators of adherence, antifungal drug resistance, and virulence. Here, we report that genetic removal of SSK1 encoding a response regulator and the mitogen-associated protein kinase HOG1 restores the susceptibility to both amphotericin B (AMB) and caspofungin (CAS) in C. auris clinical strains. The loss of SSK1 and HOG1 alters membrane lipid permeability, cell wall mannan content, and hyperresistance to cell wall-perturbing agents. Interestingly, our data reveal variable functions of SSK1 and HOG1 in different C. auris clinical isolates, suggesting a pronounced genetic plasticity affecting cell wall function, stress adaptation, and multidrug resistance. Taken together, our data suggest that targeting two-component signal transduction systems could be suitable for restoring C. auris susceptibility to antifungal drugs. IMPORTANCE Candida auris is an emerging multidrug-resistant (MDR) fungal pathogen that presents a serious global threat to human health. The Centers for Disease Control and Prevention (CDC) have classified C. auris as an urgent threat to public health for the next decade due to its major clinical and economic impact and the lack of effective antifungal drugs and because of future projections concerning new C. auris infections. Importantly, the Global Antimicrobial Resistance Surveillance System (GLASS) has highlighted the need for more robust and efficacious global surveillance schemes enabling the identification and monitoring of antifungal resistance in Candida infections. Despite the clinical relevance of C. auris infections, our overall understanding of its pathophysiology and virulence, its response to human immune surveillance, and the molecular basis of multiple antifungal resistance remains in its infancy. Here, we show a marked phenotypic plasticity of C. auris clinical isolates. Further, we demonstrate critical roles of stress response mechanisms in regulating multidrug resistance and show that cell wall architecture and composition are key elements that determine antifungal drug susceptibilities. Our data promise new therapeutic options to treat drug-refractory C. auris infections.Raju ShivarathriSabrina JenullAnton StoiberManju ChauhanRounik MazumdarAshutosh SinghFilomena NogueiraKarl KuchlerAnuradha ChowdharyNeeraj ChauhanAmerican Society for MicrobiologyarticleCandida aurisSSK1HOG1multidrug resistancecell wallMAPK signalingMicrobiologyQR1-502ENmSphere, Vol 5, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida auris SSK1 HOG1 multidrug resistance cell wall MAPK signaling Microbiology QR1-502
spellingShingle	Candida auris SSK1 HOG1 multidrug resistance cell wall MAPK signaling Microbiology QR1-502 Raju Shivarathri Sabrina Jenull Anton Stoiber Manju Chauhan Rounik Mazumdar Ashutosh Singh Filomena Nogueira Karl Kuchler Anuradha Chowdhary Neeraj Chauhan The Two-Component Response Regulator Ssk1 and the Mitogen-Activated Protein Kinase Hog1 Control Antifungal Drug Resistance and Cell Wall Architecture of <named-content content-type="genus-species">Candida auris</named-content>
description	ABSTRACT Candida auris is an emerging multidrug-resistant human fungal pathogen refractory to treatment by several classes of antifungal drugs. Unlike other Candida species, C. auris can adhere to human skin for prolonged periods of time, allowing for efficient skin-to-skin transmission in the hospital environments. However, molecular mechanisms underlying pronounced multidrug resistance and adhesion traits are poorly understood. Two-component signal transduction and mitogen-activated protein (MAP) kinase signaling are important regulators of adherence, antifungal drug resistance, and virulence. Here, we report that genetic removal of SSK1 encoding a response regulator and the mitogen-associated protein kinase HOG1 restores the susceptibility to both amphotericin B (AMB) and caspofungin (CAS) in C. auris clinical strains. The loss of SSK1 and HOG1 alters membrane lipid permeability, cell wall mannan content, and hyperresistance to cell wall-perturbing agents. Interestingly, our data reveal variable functions of SSK1 and HOG1 in different C. auris clinical isolates, suggesting a pronounced genetic plasticity affecting cell wall function, stress adaptation, and multidrug resistance. Taken together, our data suggest that targeting two-component signal transduction systems could be suitable for restoring C. auris susceptibility to antifungal drugs. IMPORTANCE Candida auris is an emerging multidrug-resistant (MDR) fungal pathogen that presents a serious global threat to human health. The Centers for Disease Control and Prevention (CDC) have classified C. auris as an urgent threat to public health for the next decade due to its major clinical and economic impact and the lack of effective antifungal drugs and because of future projections concerning new C. auris infections. Importantly, the Global Antimicrobial Resistance Surveillance System (GLASS) has highlighted the need for more robust and efficacious global surveillance schemes enabling the identification and monitoring of antifungal resistance in Candida infections. Despite the clinical relevance of C. auris infections, our overall understanding of its pathophysiology and virulence, its response to human immune surveillance, and the molecular basis of multiple antifungal resistance remains in its infancy. Here, we show a marked phenotypic plasticity of C. auris clinical isolates. Further, we demonstrate critical roles of stress response mechanisms in regulating multidrug resistance and show that cell wall architecture and composition are key elements that determine antifungal drug susceptibilities. Our data promise new therapeutic options to treat drug-refractory C. auris infections.
format	article
author	Raju Shivarathri Sabrina Jenull Anton Stoiber Manju Chauhan Rounik Mazumdar Ashutosh Singh Filomena Nogueira Karl Kuchler Anuradha Chowdhary Neeraj Chauhan
author_facet	Raju Shivarathri Sabrina Jenull Anton Stoiber Manju Chauhan Rounik Mazumdar Ashutosh Singh Filomena Nogueira Karl Kuchler Anuradha Chowdhary Neeraj Chauhan
author_sort	Raju Shivarathri
title	The Two-Component Response Regulator Ssk1 and the Mitogen-Activated Protein Kinase Hog1 Control Antifungal Drug Resistance and Cell Wall Architecture of <named-content content-type="genus-species">Candida auris</named-content>
title_short	The Two-Component Response Regulator Ssk1 and the Mitogen-Activated Protein Kinase Hog1 Control Antifungal Drug Resistance and Cell Wall Architecture of <named-content content-type="genus-species">Candida auris</named-content>
title_full	The Two-Component Response Regulator Ssk1 and the Mitogen-Activated Protein Kinase Hog1 Control Antifungal Drug Resistance and Cell Wall Architecture of <named-content content-type="genus-species">Candida auris</named-content>
title_fullStr	The Two-Component Response Regulator Ssk1 and the Mitogen-Activated Protein Kinase Hog1 Control Antifungal Drug Resistance and Cell Wall Architecture of <named-content content-type="genus-species">Candida auris</named-content>
title_full_unstemmed	The Two-Component Response Regulator Ssk1 and the Mitogen-Activated Protein Kinase Hog1 Control Antifungal Drug Resistance and Cell Wall Architecture of <named-content content-type="genus-species">Candida auris</named-content>
title_sort	two-component response regulator ssk1 and the mitogen-activated protein kinase hog1 control antifungal drug resistance and cell wall architecture of <named-content content-type="genus-species">candida auris</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/9895c8d7992a4d8dab734dccd07fb996
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The Two-Component Response Regulator Ssk1 and the Mitogen-Activated Protein Kinase Hog1 Control Antifungal Drug Resistance and Cell Wall Architecture of <named-content content-type="genus-species">Candida auris</named-content>

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