Nickel Sequestration by the Host-Defense Protein Human Calprotectin

Nakashige, Toshiki G.; Zygiel, Emily M.; Drennan, Catherine L.; Nolan, Elizabeth M.

doi:10.1021/jacs.7b01212

Cited by 100 publications

(209 citation statements)

References 72 publications

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“…However, there are few studies where P. mirabilis nickel homeostasis has been examined. Likewise, nickel sequestration by the host as a pathogen defense strategy has been proposed, but not yet conclusively demonstrated (344). Yet, there are some indications that nickel balance contributes to P. mirabilis fitness in the urinary tract.…”

Section: Virulence Factorsmentioning

confidence: 99%

Pathogenesis of Proteus mirabilis Infection

2018

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Proteus mirabilis, a Gram-negative rod-shaped bacterium most noted for its swarming motility and urease activity, frequently causes catheter-associated urinary tract infections (CAUTI) that are often polymicrobial. These infections may be accompanied by urolithiasis, development of bladder or kidney stones due to alkalinization of urine from urease-catalyzed urea hydrolysis. Adherence of the bacterium to epithelial and catheter surfaces is mediated by 17 different fimbriae, most notably MR/P fimbriae. Repressors of motility are often encoded by these fimbrial operons. Motility is mediated by flagella encoded on a single contiguous 54 kb chromosomal sequence. On agar plates, P. mirabilis undergoes a morphological conversion to a filamentous swarmer cell expressing hundreds of flagella. When swarms from different strains meet, a line of demarcation, a “Dienes line”, develops due to the killing action of each strain’s type VI secretion system. During infection, histological damage is caused by cytotoxins including hemolysin and a variety of proteases, some autotransported. The pathogenesis of infection, including assessment of individual genes or global screens for virulence or fitness factors has been assessed in murine models of ascending UTI or CAUTI using both single-species and polymicrobial models. Global gene expression studies carried out in culture and in the murine model have revealed the unique metabolism of this bacterium. Vaccines, using MR/P fimbria and its adhesin, MrpH, have been shown to be efficacious in the murine model. A comprehensive review of factors associated with urinary tract infection is presented, encompassing both historical perspectives and current advances.

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Section: Virulence Factorsmentioning

confidence: 99%

Pathogenesis of Proteus mirabilis Infection

2018

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“…Urease assay-A phenol hypochlorite assay was used to assess the urease activity of lysates (37,60). Briefly, LB starter cultures were inoculated 1:100 into W4 minimal N media (34, 61) (93mM potassium phosphate, pH 7.4, 0.4% glucose, 1.74 g/L glutamic acid, 0.83 mM MgSO4, 10 ug/mL niacin) and grown for 20 hrs.…”

Section: Cellular Uptake Of Ni-ybt-starter Cultures Ofmentioning

confidence: 99%

“…Nickel content in a host is generally low (~3 nmoles per liter (36) and ~40 nmoles per liter (13) in serum and urine, respectively), and the ability of host nickel binding proteins to competitively bind Ni(II) may pose a further challenge to infecting bacteria. One such candidate is the human innate immune protein calprotectin (S100A8/S100A9 heterodimer), which appears at bacterial infection sites and can bind Ni(II) sufficiently restrict Staphylococcus aureus and Klebsiella pneumoniae urease activity (37 Given its ability to mediate nickel import, the observation that Ybt also protects UPEC from nickel toxicity presents an apparent paradoxYbt mediates both import and detoxificationsimilar to that observed for Ybt and copper (7,8). This can be resolved by a model in which bacteria secrete Ybt in excess of local metal levels, creating an extracellular transition metal ion sink from which the secreting cell may import metalYbt complexes in a controlled manner.…”

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confidence: 99%

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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“…CP has been well studied for its Zn-withholding properties from various pathogenic organisms, including Gram-positive and Gramnegative bacteria as well as the fungus Aspergillus fumigatus, where a mutant deficient in Zn sensing shows greater susceptibility toward CP in vivo (6,(13)(14)(15)(16)(17)(18). In addition to Zn, CP can withhold Mn from bacterial pathogens in vitro and in vivo (13,14,16,19,20) and can deplete Fe and Ni from specific microbial cultures in vitro (21,22). CP comprises 40 to 60% of the total cytoplasmic protein of neutrophils, accumulates at sites of infection at concentrations of up to 1 mg ml Ϫ1 (23,24), and is an important component of neutrophil extracellular traps (NETs) released in the extracellular space during a unique form of neutrophil cell death (25,26).…”

mentioning

confidence: 99%

“…CP is a heterodimeric protein consisting of S100A8 and S100A9 subunits and acts by binding to extracellular metals using two distinct metal coordinating sites (27). Site 1 (S1) consists of six histidine residues, two from S100A8 and four from S100A9 (28,29), and has long been known to bind Zn(II) and Mn(II) (28)(29)(30)(31)(32)(33) and more recently known to bind Fe(II) and Ni(II) (21,22). Site 2 (S2) contains a canonical S100 transition metal binding site consisting of two histidines from S100A8 and a histidine and aspartate from S100A9.…”

mentioning

confidence: 99%

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

et al. 2018

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The opportunistic fungal pathogen Candida albicans acquires essential metals from the host, yet the host can sequester these micronutrients through a process known as nutritional immunity. How the host withholds metals from C. albicans has been poorly understood; here we examine the role of calprotectin (CP), a transition metal binding protein. When CP depletes bioavailable Zn from the extracellular environment, C. albicans strongly upregulates ZRT1 and PRA1 for Zn import and maintains constant intracellular Zn through numerous cell divisions. We show for the first time that CP can also sequester Cu by binding Cu(II) with subpicomolar affinity. CP blocks fungal acquisition of Cu from serum and induces a Cu starvation stress response involving SOD1 and SOD3 superoxide dismutases. These transcriptional changes are mirrored when C. albicans invades kidneys in a mouse model of disseminated candidiasis, although the responses to Cu and Zn limitations are temporally distinct. The Cu response progresses throughout 72 h, while the Zn response is short-lived. Notably, these stress responses were attenuated in CP null mice, but only at initial stages of infection. Thus, Zn and Cu pools are dynamic at the hostpathogen interface and CP acts early in infection to restrict metal nutrients from C. albicans.

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Nickel Sequestration by the Host-Defense Protein Human Calprotectin

Cited by 100 publications

References 72 publications

Pathogenesis of Proteus mirabilis Infection

Pathogenesis of Proteus mirabilis Infection

Uropathogenic enterobacteria use the yersiniabactin metallophore system to acquire nickel

Role of Calprotectin in Withholding Zinc and Copper from Candida albicans

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