ZupT Facilitates <named-content content-type="genus-species">Clostridioides difficile</named-content> Resistance to Host-Mediated Nutritional Immunity

ABSTRACT Clostridioides difficile is a spore-forming bacterium that causes severe colitis and is a major public health threat. During infection, C. difficile toxin production results in damage to the epithelium and a hyperinflammatory response. The immune response to CDI leads to robust neutrophil i...

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Autores principales:	Joseph P. Zackular, Reece J. Knippel, Christopher A. Lopez, William N. Beavers, C. Noel Maxwell, Walter J. Chazin, Eric P. Skaar
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Clostridium difficile host-pathogen interactions infectious disease nutrient transport Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/58e89e011997490d95225cdd11918de3
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spelling	oai:doaj.org-article:58e89e011997490d95225cdd11918de32021-11-15T15:29:16ZZupT Facilitates <named-content content-type="genus-species">Clostridioides difficile</named-content> Resistance to Host-Mediated Nutritional Immunity10.1128/mSphere.00061-202379-5042https://doaj.org/article/58e89e011997490d95225cdd11918de32020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00061-20https://doaj.org/toc/2379-5042ABSTRACT Clostridioides difficile is a spore-forming bacterium that causes severe colitis and is a major public health threat. During infection, C. difficile toxin production results in damage to the epithelium and a hyperinflammatory response. The immune response to CDI leads to robust neutrophil infiltration at the sight of infection and the deployment of numerous antimicrobials. One of the most abundant host immune factors associated with CDI is calprotectin, a metal-chelating protein with potent antimicrobial activity. Calprotectin is essential to the innate immune response to C. difficile and increasing levels of calprotectin correlate with disease severity in both adults and children with CDI. The fact that C. difficile persists in the presence of high levels of calprotectin suggests that this organism may deploy strategies to compete with this potent antimicrobial factor for essential nutrient metals during infection. In this report, we demonstrate that a putative zinc (Zn) transporter, ZupT, is employed by C. difficile to survive calprotectin-mediated metal limitation. ZupT is highly expressed in the presence of calprotectin and is required to protect C. difficile against calprotectin-dependent growth inhibition. When competing against wild-type C. difficile, zupT mutants show a defect in colonization and persistence in a murine model of infection. Together these data demonstrate that C. difficile utilizes a metal import system to combat nutritional immunity during CDI and suggest that strategies targeting nutrient acquisition in C. difficile may have therapeutic potential. IMPORTANCE During infection, pathogenic organisms must acquire essential transition metals from the host environment. Through the process of nutritional immunity, the host employs numerous strategies to restrict these key nutrients from invading pathogens. In this study, we describe a mechanism by which the important human pathogen Clostridioides difficile resists transition-metal limitation by the host. We report that C. difficile utilizes a zinc transporter, ZupT, to compete with the host protein calprotectin for nutrient zinc. Inactivation of this transporter in C. difficile renders this important pathogen sensitive to host-mediated metal restriction and confers a fitness disadvantage during infection. Our study demonstrates that targeting nutrient metal transport proteins in C. difficile is a potential avenue for therapeutic development.Joseph P. ZackularReece J. KnippelChristopher A. LopezWilliam N. BeaversC. Noel MaxwellWalter J. ChazinEric P. SkaarAmerican Society for MicrobiologyarticleClostridium difficilehost-pathogen interactionsinfectious diseasenutrient transportMicrobiologyQR1-502ENmSphere, Vol 5, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Clostridium difficile host-pathogen interactions infectious disease nutrient transport Microbiology QR1-502
spellingShingle	Clostridium difficile host-pathogen interactions infectious disease nutrient transport Microbiology QR1-502 Joseph P. Zackular Reece J. Knippel Christopher A. Lopez William N. Beavers C. Noel Maxwell Walter J. Chazin Eric P. Skaar ZupT Facilitates <named-content content-type="genus-species">Clostridioides difficile</named-content> Resistance to Host-Mediated Nutritional Immunity
description	ABSTRACT Clostridioides difficile is a spore-forming bacterium that causes severe colitis and is a major public health threat. During infection, C. difficile toxin production results in damage to the epithelium and a hyperinflammatory response. The immune response to CDI leads to robust neutrophil infiltration at the sight of infection and the deployment of numerous antimicrobials. One of the most abundant host immune factors associated with CDI is calprotectin, a metal-chelating protein with potent antimicrobial activity. Calprotectin is essential to the innate immune response to C. difficile and increasing levels of calprotectin correlate with disease severity in both adults and children with CDI. The fact that C. difficile persists in the presence of high levels of calprotectin suggests that this organism may deploy strategies to compete with this potent antimicrobial factor for essential nutrient metals during infection. In this report, we demonstrate that a putative zinc (Zn) transporter, ZupT, is employed by C. difficile to survive calprotectin-mediated metal limitation. ZupT is highly expressed in the presence of calprotectin and is required to protect C. difficile against calprotectin-dependent growth inhibition. When competing against wild-type C. difficile, zupT mutants show a defect in colonization and persistence in a murine model of infection. Together these data demonstrate that C. difficile utilizes a metal import system to combat nutritional immunity during CDI and suggest that strategies targeting nutrient acquisition in C. difficile may have therapeutic potential. IMPORTANCE During infection, pathogenic organisms must acquire essential transition metals from the host environment. Through the process of nutritional immunity, the host employs numerous strategies to restrict these key nutrients from invading pathogens. In this study, we describe a mechanism by which the important human pathogen Clostridioides difficile resists transition-metal limitation by the host. We report that C. difficile utilizes a zinc transporter, ZupT, to compete with the host protein calprotectin for nutrient zinc. Inactivation of this transporter in C. difficile renders this important pathogen sensitive to host-mediated metal restriction and confers a fitness disadvantage during infection. Our study demonstrates that targeting nutrient metal transport proteins in C. difficile is a potential avenue for therapeutic development.
format	article
author	Joseph P. Zackular Reece J. Knippel Christopher A. Lopez William N. Beavers C. Noel Maxwell Walter J. Chazin Eric P. Skaar
author_facet	Joseph P. Zackular Reece J. Knippel Christopher A. Lopez William N. Beavers C. Noel Maxwell Walter J. Chazin Eric P. Skaar
author_sort	Joseph P. Zackular
title	ZupT Facilitates <named-content content-type="genus-species">Clostridioides difficile</named-content> Resistance to Host-Mediated Nutritional Immunity
title_short	ZupT Facilitates <named-content content-type="genus-species">Clostridioides difficile</named-content> Resistance to Host-Mediated Nutritional Immunity
title_full	ZupT Facilitates <named-content content-type="genus-species">Clostridioides difficile</named-content> Resistance to Host-Mediated Nutritional Immunity
title_fullStr	ZupT Facilitates <named-content content-type="genus-species">Clostridioides difficile</named-content> Resistance to Host-Mediated Nutritional Immunity
title_full_unstemmed	ZupT Facilitates <named-content content-type="genus-species">Clostridioides difficile</named-content> Resistance to Host-Mediated Nutritional Immunity
title_sort	zupt facilitates <named-content content-type="genus-species">clostridioides difficile</named-content> resistance to host-mediated nutritional immunity
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/58e89e011997490d95225cdd11918de3
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ZupT Facilitates <named-content content-type="genus-species">Clostridioides difficile</named-content> Resistance to Host-Mediated Nutritional Immunity

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