Coordinated Zinc Homeostasis Is Essential for the Wild-Type Virulence of Brucella abortus

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dc.contributor.authorSheehan, Lauren M.en
dc.contributor.authorBudnick, James A.en
dc.contributor.authorRoop, R. Martin IIen
dc.contributor.authorCaswell, Clayton C.en
dc.contributor.departmentVirginia Tech. Virginia-Maryland College of Veterinary Medicine. Department of Biomedical Sciences and Pathobiology, Center for Molecular Medicine and Infectious Diseasesen
dc.date.accessed2015-10-01en
dc.date.accessioned2015-11-28T21:53:47Zen
dc.date.available2015-11-28T21:53:47Zen
dc.date.issued2015-02-17en
dc.description.abstractMetal homeostasis in bacterial cells is a highly regulated process requiring intricately coordinated import and export, as well as precise sensing of intracellular metal concentrations. The uptake of zinc (Zn) has been linked to the virulence of Brucella abortus; however, the capacity of Brucella strains to sense Zn levels and subsequently coordinate Zn homeostasis has not been described. Here, we show that expression of the genes encoding the zinc uptake system ZnuABC is negatively regulated by the Znsensing Fur family transcriptional regulator, Zur, by direct interactions between Zur and the promoter region of znuABC. Moreover, the MerR-type regulator, ZntR, controls the expression of the gene encoding the Zn exporter ZntA by binding directly to its promoter. Deletion of zur or zntR alone did not result in increased zinc toxicity in the corresponding mutants; however, deletion of zntA led to increased sensitivity to Zn but not to other metals, such as Cu and Ni, suggesting that ZntA is a Zn-specific exporter. Strikingly, deletion of zntR resulted in significant attenuation of B. abortus in a mouse model of chronic infection, and subsequent experiments revealed that overexpression of zntA in the zntR mutant is the molecular basis for its decreased virulence. IMPORTANCE The importance of zinc uptake for Brucella pathogenesis has been demonstrated previously, but to date, there has been no description of how overall zinc homeostasis is maintained and genetically controlled in the brucellae. The present work defines the predominant zinc export system, as well as the key genetic regulators of both zinc uptake and export in Brucella abortus. Moreover, the data show the importance of precise coordination of the zinc homeostasis systems as disregulation of some elements of these systems leads to the attenuation of Brucella virulence in a mouse model. Overall, this study advances our understanding of the essential role of zinc in the pathogenesis of intracellular bacteria.en
dc.description.sponsorshipVirginia-Maryland College of Veterinary Medicineen
dc.description.sponsorshipVirginia Tech. Fralin Life Science Instituteen
dc.description.sponsorshipAI48499en
dc.description.sponsorshipAI63516en
dc.description.sponsorshipNational Institute of Allergy and Infectious Diseasesen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationSheehan, Lauren M., et al. (2015). Coordinated Zinc Homeostasis Is Essential for the Wild-Type Virulence of Brucella abortus. Journal of Bacteriology, 197(9), 1582-1591. doi:10.1128/jb.02543-14en
dc.identifier.doihttps://doi.org/10.1128/jb.02543-14en
dc.identifier.issn0021-9193en
dc.identifier.urihttp://hdl.handle.net/10919/64213en
dc.identifier.urlhttp://jb.asm.org/content/197/9/1582en
dc.language.isoenen
dc.publisherAmerican Society for Microbiologyen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.titleCoordinated Zinc Homeostasis Is Essential for the Wild-Type Virulence of Brucella abortusen
dc.title.serialJournal of Bacteriologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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