Human Urinary Composition Controls Antibacterial Activity of Siderocalin*

Shields-Cutler, Robin R.; Crowley, Jan R.; Hung, Chia-Suei; Stapleton, Ann E.; Aldrich, Courtney C.; Marschall, Jonas; Henderson, Jeffrey P.

doi:10.1074/jbc.m115.645812

Cited by 48 publications

(89 citation statements)

References 53 publications

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“…[6][7][8][9] In particular UPEC have evolved a complex mechanism to chelate iron via siderophores, and several studies have revealed that UPEC have more iron chelators than most bacterial pathogens. 7,[9][10][11][12][13] Consistent with this, UPEC growth is impeded if the bacteria are prevented from acquiring iron. 6,9,14 However, eukaryotic cells have evolved elaborate methods of iron sequestration, storage, and release.…”

Section: Introductionmentioning

confidence: 53%

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Bauckman

Mysorekar

2016

Autophagy

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Autophagy is a cellular recycling pathway, which in many cases, protects host cells from infections by degrading pathogens. However, uropathogenic Escherichia coli (UPEC), the predominant cause of urinary tract infections (UTIs), persist within the urinary tract epithelium (urothelium) by forming reservoirs within autophagosomes. Iron is a critical nutrient for both host and pathogen, and regulation of iron availability is a key host defense against pathogens. Iron homeostasis depends on the shuttling of iron-bound ferritin to the lysosome for recycling, a process termed ferritinophagy (a form of selective autophagy). Here, we demonstrate for the first time that UPEC shuttles with ferritin-bound iron into the autophagosomal and lysosomal compartments within the urothelium. Iron overload in urothelial cells induces ferritinophagy in an NCOA4-dependent manner causing increased iron availability for UPEC, triggering bacterial overproliferation and host cell death. Addition of even moderate levels of iron is sufficient to increase and prolong bacterial burden. Furthermore, we show that lysosomal damage due to iron overload is the specific mechanism causing host cell death. Significantly, we demonstrate that host cell death and bacterial burden can be reversed by inhibition of autophagy or inhibition of iron-regulatory proteins, or chelation of iron. Together, our findings suggest that UPEC persist in host cells by taking advantage of ferritinophagy. Thus, modulation of iron levels in the bladder may provide a therapeutic avenue to controlling UPEC persistence, epithelial cell death, and recurrent UTIs.

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Section: Introductionmentioning

confidence: 53%

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Bauckman

Mysorekar

2016

Autophagy

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“…All participants provided written informed consent for the sample collection and following analysis, prior to inclusion in the study. Study design, inclusion and exclusion criteria, and sample preparation were previously described (14,86). β-Hemolytic E. coli isolates from urine cultures with 10 5 or more CFU/ml were selected from the cohort for analysis.…”

Section: Methodsmentioning

confidence: 99%

Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria

Ohlemacher¹,

Giblin²,

d’Avignon³

et al. 2017

Journal of Clinical Investigation

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“…These studies, combining chemical screening 54 and natural product approaches proved the putative ligands as naturally occurring iron “buffers” in the human urine 66 . Using a LC-MS based metabolomic analysis, catechols have been further confirmed existing in human urine and controlling urinary NGAL antimicrobial activity recently 67 . The combination of the three studies support the notion that simple catechols should be considered naturally occurring binding partners of NGAL.…”

Section: The Ligands Of Ngalmentioning

confidence: 97%

“…Detailed reviews and comments on the catechols could be found in different journals 17,64–67 . In the study, simple catechols such as catechol ( 51 ), 3-methylcatechol ( 52 ), 4-methylcatechol ( 53 ), and pyrogallol ( 54 ) (Fig.…”

Section: The Ligands Of Ngalmentioning

confidence: 99%

The ligands of neutrophil gelatinase-associated lipocalin

Bao

Barasch

2015

RSC Adv.

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Neutrophil gelatinase associated lipocalin (NGAL), was originally identified in neutrophil granules as a heterodimer complex with gelatinase B (matrix metalloproteinase 9, MMP9), but more recently has been found to be secreted by damaged epithelial cells. Ngal is a member of the lipocalin family and subsequently named as lipocalin 2 on the basis of structural similarity with other members of the lipocalin family and its potential association with hydrophobic retinol and cholesterol oleate more strongly than their hydrophilic counterparts. In 2002, a landmark paper suggested that Ngal is a bacteriostatic agent which blocks iron acquisition by interacting with a number of bacterial siderophores, especially enterobactin. Since then, more siderophore-carrying functions have been reported than the possibility of hydrophobic ligand transport. In this setting, Ngal was renamed Siderocalin. Functions of siderocalin include not only bacteriostatic activity but potentially as a mediator of cell growth and differentiation; some of these functions appear to be referable to the holo siderocalin:siderophore:iron complex and recent work suggests that metabolic products may act as mammalian siderophores bound by Ngal. While still speculative, it may be that the mammalian siderophores can establish the missing link between Ngal and a number of its functions in vivo. This review provides an overview of the discoveries of the different ligands of Ngal and consequently related functions. Hydrophobic ligands, bacterial siderophores as well as their modified structures (synthetic siderophores), and mammalian siderophores are summarized.

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Human Urinary Composition Controls Antibacterial Activity of Siderocalin*

Cited by 48 publications

References 53 publications

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Ferritinophagy drives uropathogenicEscherichia colipersistence in bladder epithelial cells

Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria

The ligands of neutrophil gelatinase-associated lipocalin

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