The Transcriptional Regulator Np20 Is the Zinc Uptake Regulator in Pseudomonas aeruginosa

Ellison, Matthew L.; Farrow, John M.; Parrish, Whitney; Danell, Allison S.; Pesci, Everett C.

doi:10.1371/journal.pone.0075389

Cited by 51 publications

(80 citation statements)

References 52 publications

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“…As bacterial responses to chelating agents are sometimes ambiguous 56 , we analyzed growth of a PA14 mutant strain lacking znuA in a chemically defined minimal medium containing only contaminant traces of zinc. In line with the results of Ellison et al 55 , the mutant strain exhibited a modest growth defect (Figure 1A) and a more marked phenotype could be observed only in minimal medium agar plates supplemented with EDTA (Figure 1b), a result possibly favored by the ability of the solid agar support to limit zinc availability to bacteria 57 . The small impact of znuA deletion on bacterial growth is accompanied by the substantial equality of the intracellular zinc content between the wild-type and the mutant strains grown in minimal medium (Figure 4).…”

Section: Discussionsupporting

confidence: 89%

The capability of Pseudomonas aeruginosa to recruit zinc under conditions of limited metal availability is affected by inactivation of the ZnuABC transporter

et al. 2015

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The ability of a large number of bacterial pathogens to multiply in the infected host and cause disease is dependent on their ability to express high affinity zinc importers. In many bacteria ZnuABC, a transporter of the ABC family, plays a central role in the process of zinc uptake in zinc poor environments, including the tissues of the infected host. To initiate an investigation into the relevance of the zinc uptake apparatus for Pseudomonas aeruginosa pathogenicity, we have generated a znuA mutant in the PA14 strain. We have found that this mutant strain displays a limited growth defect in zinc depleted media. The znuA mutant strain is more sensitive than the wild type strain to calprotectin-mediated growth inhibition, but both the strains are highly resistant to this zinc sequestering antimicrobial protein. Moreover, intracellular zinc content is not evidently affected by inactivation of the ZnuABC transporter. These findings suggest that P. aeruginosa is equipped with redundant mechanisms for the acquisition of zinc that might favor P. aeruginosa colonization of environments containing low levels of this metal. Nonetheless, deletion of znuA affects alginate production, reduces the activity of extracellular zinc-containing proteases, including LasA, LasB and Protease IV, and decreases the ability of P. aeruginosa to disseminate during systemic infections. These results indicate that efficient zinc acquisition is critical for the expression of various virulence features typical of P. aeruginosa and that ZnuABC also plays an important role in zinc homeostasis in this microorganism.

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Section: Discussionsupporting

confidence: 89%

The capability of Pseudomonas aeruginosa to recruit zinc under conditions of limited metal availability is affected by inactivation of the ZnuABC transporter

et al. 2015

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“…1C). These data indicate that Zur serves as a transcriptional repressor, and this is in line with what other investigators have observed, with Zur negatively controlling znu expression in several diverse bacteria, including Bacillus subtilis (26), Escherichia coli (27), and Pseudomonas aeruginosa (28). Of interest, mRNA levels for zntA, which encodes the putative Zn exporter, were also significantly elevated in the zur mutant.…”

Section: Resultssupporting

confidence: 91%

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

et al. 2015

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Metal 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. IMPORTANCEThe 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.T he pathogenic alphaproteobacterium Brucella abortus preferentially infects cattle, bison, and elk (1), but the bacteria are also highly efficient at infecting humans. In order to establish a chronic infection in these hosts, the brucellae must survive and replicate within host macrophages (2). While the macrophage serves as the niche for Brucella during a chronic infection, the intracellular environment of these phagocytic immune cells is inhospitable as the bacteria are bombarded with a variety of environmental stresses, including exposure to reactive oxygen species (ROS), low pH, limited oxygen availability, and nutrient deprivation (3). Notwithstanding, the brucellae have evolved multiple strategies to cope with the harsh intramacrophagic environment and ultimately establish a replicative niche in these cells.With regard to the nutrient limitation experienced by the brucellae within macrophages, metal cations are likely found in extremely low concentrations, and, in fact, macrophages produce transporters, such as the NRAMP family of transp...

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“…Like many bacteria (Patzer and Hantke, 1998), it possesses a Zn 21 uptake system known as ZnuABC (Ellison et al, 2013), made up of members of the ABC transporter family of proteins. Like many bacteria (Patzer and Hantke, 1998), it possesses a Zn 21 uptake system known as ZnuABC (Ellison et al, 2013), made up of members of the ABC transporter family of proteins.…”

Section: Zinc (Zn)mentioning

confidence: 99%

“…Concerning the uptake across the cytoplasmic membrane, different approaches have shown that P. aeruginosa has in its genome different Zn 21 uptake pathway. Like many bacteria (Patzer and Hantke, 1998), it possesses a Zn 21 uptake system known as ZnuABC (Ellison et al, 2013), made up of members of the ABC transporter family of proteins. This system is composed of a Zn-binding periplasmic protein (ZnuA, PA5498), an inner membrane permease (ZnuB, PA5501) and an ATPase (ZnuC, PA5500).…”

Section: Zinc (Zn)mentioning

confidence: 99%

An overview of the biological metal uptake pathways in Pseudomonas aeruginosa

Schalk

Cunrath

2016

Environmental Microbiology

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Biological metal ions, including Co, Cu, Fe, Mg, Mn, Mo, Ni and Zn ions, are necessary for the survival and the growth of all microorganisms. Their biological functions are linked to their particular chemical properties: they play a role in structuring macromolecules and/or act as co-factors catalyzing diverse biochemical reactions. These metal ions are also essential for microbial pathogens during infection: they are involved in bacterial metabolism and various virulence factor functions. Therefore, during infection, bacteria need to acquire biological metal ions from the host such that there is competition for these ions between the bacterium and the host. Evidence is increasingly emerging of "nutritional immunity" against pathogens in the hosts; this includes strategies making access to metals difficult for infecting bacteria. It is clear that biological metals play key roles during infection and in the battle between the pathogens and the host. Here, we summarize current knowledge about the strategies used by Pseudomonas aeruginosa to access the various biological metals it requires. P. aeruginosa is a medically significant Gram-negative bacterial opportunistic pathogen that can cause severe chronic lung infections in cystic fibrosis patients and that is responsible for nosocomial infections worldwide.

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The Transcriptional Regulator Np20 Is the Zinc Uptake Regulator in Pseudomonas aeruginosa

Cited by 51 publications

References 52 publications

The capability of Pseudomonas aeruginosa to recruit zinc under conditions of limited metal availability is affected by inactivation of the ZnuABC transporter

The capability of Pseudomonas aeruginosa to recruit zinc under conditions of limited metal availability is affected by inactivation of the ZnuABC transporter

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

An overview of the biological metal uptake pathways in Pseudomonas aeruginosa

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