The <scp><i>Y</i></scp><i>ersinia pestis</i> siderophore, yersiniabactin, and the <scp>ZnuABC</scp> system both contribute to zinc acquisition and the development of lethal septicaemic plague in mice

Bobrov, Alexander G.; Kirillina, Olga; Fetherston, Jacqueline D.; Miller, Michael C.; Burlison, Joseph A.; Perry, Robert D.

doi:10.1111/mmi.12693

Cited by 130 publications

(162 citation statements)

References 112 publications

(232 reference statements)

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“…While TonB/ExbB/ExbD-dependent transport systems such as FyuA are classically associated with iron import, they have also been implicated in nickel uptake by H. pylori (51). This Ni-Ybt import pathway is distinct from the putative zinc import activity associated with the Yersinia HPI in Y. pestis that is thought to proceed via YbtX (52,53). Where metal-Ybt import and trafficking pathways diverge to direct each ion to its distinctive metalloenzymes or storage proteins remains unclear.…”

Section: Discussionmentioning

confidence: 95%

Uropathogenic enterobacteria use the yersiniabactin metallophore system to acquire nickel

Robinson¹,

Lowe²,

Koh³

et al. 2018

Journal of Biological Chemistry

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Invasive gram-negative bacteria often express multiple virulence-associated metal ion chelators to combat host-mediated metal deficiencies. Escherichia coli, Klebsiella, and Yersinia pestis isolates encoding the Yersinia High Pathogenicity Island (HPI) secrete yersiniabactin (Ybt), a metallophore originally shown to chelate iron ions during infection. However, our recent demonstration that Ybt also scavenges copper ions during infection led us to question whether it might be capable of retrieving other metals as well. Here, we find that uropathogenic E. coli also use Ybt to bind extracellular nickel ions. Using quantitative mass spectrometry, we show that the canonical metal-Ybt import pathway internalizes the resulting Ni-Ybt complexes, extracts the nickel, and releases metal-free Ybt back to the extracellular space. We find that E. coli and Klebsiella direct the nickel liberated from this pathway to intracellular nickel enzymes. Thus, Ybt may provide access to nickel that is inaccessible to the conserved NikABCDE permease system. Nickel should be considered alongside iron and copper as a plausible substrate for Ybt-mediated metal import by enterobacteria during human infections.E. coli and related enterobacteria are the predominant cause of human urinary tract infections (UTIs) and contribute substantially to the worldwide rise in antibiotic-resistant infections (1). Clinical enterobacterial isolates often possess additional, non-essential, virulenceassociated genes. Prominent among these is the Yersinia high pathogenicity island (HPI), which encodes the biosynthetic machinery to make the specialized metabolites yersiniabactin (Ybt) and escherichelin (2). Direct mass spectrometric detection of urinary Ybt in UTI patients, serological markers, transcriptional signatures, and experimental infection models all indicate active expression of Yersinia HPI proteins during UTI pathogenesis (3-7).Although initially understood as a siderophore-a chelator that binds Fe(III) for bacterial use-Ybt has recently been appreciated to exhibit a broader metal ion binding repertoire. Copper-Ybt complexes were observed in E. coli UTI patients and were connected to protection of E. coli from copper toxicity (7), an example of biological metal passivation. Because copper is an important nutrient, complete sequestration of copper ions by Ybt could starve uropathogenic E. coli (UPEC) of copper. However, UPEC retain nutritional access to Ybt-bound copper and iron by importing the metal-Ybt complexes in a controlled manner, extracting the metal, and using it to support metal-dependent cellular functions (8). These findings implicate Ybt as an agent of nutritional passivation, a biological strategy in which metal ion toxicity is minimized Ybt-mediated nickel acquisition 2 while nutritional access is preserved. In this manner, Ybt acts as an extracellular metal ion sink, with subsequent entry into the cell occurring as a controlled process. Whether this nutritional passivation activity of Ybt extends to biological metal ions beyon...

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Section: Discussionmentioning

confidence: 95%

Uropathogenic enterobacteria use the yersiniabactin metallophore system to acquire nickel

Robinson¹,

Lowe²,

Koh³

et al. 2018

Journal of Biological Chemistry

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“…The genes ybtA and fyuA, which encode an AraC-like transcriptional activator of fyuA and the yersiniabactin receptor FyuA, respectively, are highlighted. Genes irp2, irp1, ybtU, ybtT, ybtE, and ybtS encode proteins involved in yersiniabactin synthesis, ybtP and ybtQ encode proteins that facilitate yersiniabactin transport across the inner membrane, and ybtX encodes a protein that contributes to yersiniabactinmediated zinc acquisition (52,53).…”

Section: Resultsmentioning

confidence: 99%

Blocking Yersiniabactin Import Attenuates Extraintestinal Pathogenic Escherichia coli in Cystitis and Pyelonephritis and Represents a Novel Target To Prevent Urinary Tract Infection

et al. 2015

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The emergence and spread of extended-spectrum beta-lactamases and carbapenemases among common bacterial pathogens are threatening our ability to treat routine hospital-and community-acquired infections. With the pipeline for new antibiotics virtually empty, there is an urgent need to develop novel therapeutics. Bacteria require iron to establish infection, and specialized pathogen-associated iron acquisition systems like yersiniabactin, common among pathogenic species in the family Enterobacteriaceae, including multidrug-resistant Klebsiella pneumoniae and pathogenic Escherichia coli, represent potentially novel therapeutic targets. Although the yersiniabactin system was recently identified as a vaccine target for uropathogenic E. coli (UPEC)-mediated urinary tract infection (UTI), its contribution to UPEC pathogenesis is unknown. Using an E. coli mutant (strain 536⌬fyuA) unable to acquire yersiniabactin during infection, we established the yersiniabactin receptor as a UPEC virulence factor during cystitis and pyelonephritis, a fitness factor during bacteremia, and a surface-accessible target of the experimental FyuA vaccine. In addition, we determined through transcriptome sequencing (RNA-seq) analyses of RNA from E. coli causing cystitis in women that iron acquisition systems, including the yersiniabactin system, are highly expressed by bacteria during natural uncomplicated UTI. Given that yersiniabactin contributes to the virulence of several pathogenic species in the family Enterobacteriaceae, including UPEC, and is frequently associated with multidrug-resistant strains, it represents a promising novel target to combat antibiotic-resistant infections.W idespread and increasing antibiotic resistance among bacterial pathogens that cause some of our most common health care-associated and community-acquired infections is jeopardizing our ability to prevent and treat routine infectious diseases (1). Two pathogens of particular concern are uropathogenic Escherichia coli (UPEC), which causes the majority (80%) of uncomplicated urinary tract infections (UTI) (2), and Klebsiella pneumoniae, a frequent cause of hospital-acquired pneumonia and UTI (3). Without adequate treatment, both UPEC and K. pneumoniae can breach epithelial and endothelial barriers to gain access to the bloodstream, causing life-threatening bacteremia (4). E. coli rates of resistance to fluoroquinolones and third-generation cephalosporins now exceed 50% in 5 of 6 global regions, and similar resistance rates were reported for K. pneumoniae worldwide (5). Unfortunately, the treatment of severe infections caused by these species must rely on carbapenems, the last resort to treat severe community-and hospital-acquired infections (6). Not only are these antibacterial compounds more expensive and less available in resource-constrained settings, but their extended use contributes to the spread of carbapenem-resistant Enterobacteriaceae (CRE), a serious global public health concern (7).Increasing rates of antimicrobial resistance and limited new therapeut...

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“…N.meningitidis effectively undermines an important defense mechanism used by the host and utilized it in its favor [94]. Yersinia pestis utilizes siderophore yersiniabactin (Ybt) as a zincophore and ZnuABC, which are the high -affinity zinc transporter found in bacteria and fungi, to acquire zinc and develop a lethal infection in a septicemic plague mouse model [95]. Salmonella typhimurium can also overcome calprotectin-mediated zinc chelation by expressing ZnuABC, thereby allowing it to compete with commensal bacteria and thrive in the inflamed gut [96].…”

Section: Zinc In Infection a Nutritional Immunitymentioning

confidence: 99%

Zinc in Infection and Inflammation

Gammoh¹,

Rink²

2017

Preprint

187

139

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Abstract:Micronutrient homeostasis is a key factor in maintaining a healthy immune system. Zinc is an essential micronutrient that is involved in the regulation of the innate and adaptive immune responses. The main cause of zinc deficiency is malnutrition. Zinc deficiency leads to cell-mediated immune dysfunctions among other manifestations. Consequently, such dysfunctions lead to a worse outcome in the response towards bacterial infection and sepsis. For instance, zinc is an essential component of the pathogen-eliminating signal transduction pathways leading to neutrophil extracellular traps formation, as well as inducing cell-mediated immunity over humoral immunity by regulating specific factors or differentiation. Additionally, zinc deficiency plays a role in inflammation, mainly elevating inflammatory response as well as damage to host tissue. Zinc is involved in the modulation of the proinflammatory response by targeting Nuclear Factor Kappa B, a transcription factor that is the master regulator of proinflammatory responses. It is also involved in controlling oxidative stress and regulating inflammatory cytokines. Zinc plays an intricate function during an immune response and its homeostasis is critical for sustaining proper immune function. This review will summarize the latest findings concerning the role of this micronutrient during the course of infections and inflammatory response and how the immune system modulates zinc depending on different stimuli.

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The Yersinia pestis siderophore, yersiniabactin, and the ZnuABC system both contribute to zinc acquisition and the development of lethal septicaemic plague in mice

Cited by 130 publications

References 112 publications

Uropathogenic enterobacteria use the yersiniabactin metallophore system to acquire nickel

Uropathogenic enterobacteria use the yersiniabactin metallophore system to acquire nickel

Blocking Yersiniabactin Import Attenuates Extraintestinal Pathogenic Escherichia coli in Cystitis and Pyelonephritis and Represents a Novel Target To Prevent Urinary Tract Infection

Zinc in Infection and Inflammation

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