α–Intercalated cells defend the urinary system from bacterial infection

Paragas, Neal; Kulkarni, Ritwij; Werth, Max; Schmidt‐Ott, Kai M.; Forster, Catherine S.; Deng, Rong; Zhang, Qingyin; Singer, Eugenia; Klose, Alexander D.; Shen, Tian; Francis, Kevin P.; Ray, Sunetra; Vijayakumar, Soundarapandian; Seward, Samuel L.; Bovino, Mary E.; Xu, Katherine; Takabe, Yared; Amaral, Fábio E.; Mohan, Sumit; Wax, Rebecca; Corbin, Kaitlyn; Sanna‐Cherchi, Simone; Mori, Kiyoshi; Johnson, Lynne; Nickolas, Thomas L.; D’Agati, Vivette D.; Lin, Chyuan-Sheng; Qiu, Andong; Al‐Awqati, Qais; Ratner, Adam J.; Barasch, Jonathan

doi:10.1172/jci71630

Cited by 129 publications

(119 citation statements)

References 117 publications

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“…However, urine creatinine is an imperfect method of standardization for uNGAL in the setting of UTI. Urine creatinine comes from the filtrate at the level ofthe glomerulus, whereas uNGAL is produced by the collecting ducts [23], and is essentially free from glomerular filtration [24]. Similar to acute kidney injury, we show that uNGAL levels are increased in UTI regardless of whether or not NGAL is normalized [9], although the nonnormalized form of uNGAL has a greater sensitivity compared with the normalized form, which is more specific.…”

Section: Discussionmentioning

confidence: 88%

Predictive ability of NGAL in identifying urinary tract infection in children with neurogenic bladders

Forster

Jackson

et al. 2018

Pediatr Nephrol

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Background Distinguishing between urinary tract infection (UTI) and colonization (UTC) in patients with neurogenic bladders who require clean intermittent catheterization (CIC) is difficult. Urinary neutrophil gelatinase-associated lipocalin concentrations (uNGAL) are increased in UTIs. Our objective was to determine the predictive accuracy of uNGAL for UTI in CIC-dependent children. Methods Cross-sectional study of CIC-dependent patients from August, 2015 to November, 2016. UTI was defined as (1) growth of ≥ 50,000 cfu/mL of a uropathogen, (2) > 10 urinary white blood cells/hpf, and (3) ≥ 2 of the following: temperature > 38 °C, abdominal pain, back pain, worsened incontinence, pain with catheterization, or malodorous/cloudy urine. Positive urine cultures that did not meet these criteria were grouped as UTC, and negative cultures were grouped as no growth. Results Two hundred one patients were included (no growth = 100, UTC = 77, UTI = 24). Median (interquartile range) uNGAL was higher in the UTI group (UTI 1361 (931, 2516) μg/g creatinine, UTC 246 (106, 548) μg/g creatinine, no growth 36 (11, 179) μg/g creatinine, p < 0.01 for all comparisons). The area under the ROC curve for uNGAL for UTI versus no UTI was 0.89, 95% CI (0.80–0.98). Conclusion uNGAL is elevated in CIC-dependent children with UTI compared to those with negative cultures and those with UTC.

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Section: Discussionmentioning

confidence: 88%

Predictive ability of NGAL in identifying urinary tract infection in children with neurogenic bladders

Forster

Jackson

et al. 2018

Pediatr Nephrol

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“…The neutrophil gelatinase-associated lipocalin (NGAL) protein binds bacterial siderophores such as enterochelin 19,20 . NGAL, which is produced by α-intercalated cells in the kidney, was recently shown to restrict the growth of UPEC in the urinary tracts of both humans and mice 21 . During UPEC infection, mice deficient in NGAL or α-intercalated cells showed increased susceptibility to infection compared with wild-type mice 21 .…”

Section: Innate Immune Responsesmentioning

confidence: 99%

“…NGAL, which is produced by α-intercalated cells in the kidney, was recently shown to restrict the growth of UPEC in the urinary tracts of both humans and mice 21 . During UPEC infection, mice deficient in NGAL or α-intercalated cells showed increased susceptibility to infection compared with wild-type mice 21 . A variety of antimicrobial peptides (AMPs) — such as cathelici-din-related AMPs (for example, LL-37 (also known as CAMP)) 22 , β-defensin 1 (REF.…”

Section: Innate Immune Responsesmentioning

confidence: 99%

The nature of immune responses to urinary tract infections

2015

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The urinary tract is constantly exposed to microorganisms that inhabit the gastrointestinal tract, but generally the urinary tract resists infection by gut microorganisms. This resistance to infection is mainly ascribed to the versatility of the innate immune defences in the urinary tract as the adaptive immune responses are limited, particularly when only the lower urinary tract is infected. In recent years, as the strengths and weaknesses of the immune system of the urinary tract have emerged and as the virulence attributes of uropathogens are recognized, several potentially effective and unconventional strategies to contain or prevent urinary tract infections have emerged.

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“…Nephrons secrete lipocalin into urine to hamper enterobactin-dependent iron uptake by UPEC during UTI (39)(40)(41). By utilizing lipocalin-resistant siderophores such as yersiniabactin and salmochelin, UPEC continues to acquire iron within the urinary tract.…”

Section: Fig 12mentioning

confidence: 99%

Copper Is a Host Effector Mobilized to Urine during Urinary Tract Infection To Impair Bacterial Colonization

et al. 2017

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Urinary tract infection (UTI) is a major global infectious disease affecting millions of people annually. Human urinary copper (Cu) content is elevated during UTI caused by uropathogenic Escherichia coli (UPEC). UPEC upregulates the expression of Cu efflux genes during clinical UTI in patients as an adaptive response to host-derived Cu. Whether Cu is mobilized to urine as a host response to UTI and its role in protection against UTI remain unresolved. To address these questions, we tested the hypothesis that Cu is a host effector mobilized to urine during UTI to limit bacterial growth. Our results reveal that Cu is mobilized to urine during UTI caused by the major uropathogens Proteus mirabilis and Klebsiella pneumoniae, in addition to UPEC, in humans. Ceruloplasmin, a Cu-containing ferroxidase, is found at higher levels in UTI urine than in healthy control urine and serves as the molecular source of urinary Cu during UTI. Our results demonstrate that ceruloplasmin decreases the bioavailability of iron in urine by a transferrin-dependent mechanism. Experimental UTI with UPEC in nonhuman primates recapitulates the increased urinary Cu content observed during clinical UTI. Furthermore, Cu-deficient mice are highly colonized by UPEC, indicating that Cu is involved in the limiting of bacterial growth within the urinary tract. Collectively, our results indicate that Cu is a host effector that is involved in protection against pathogen colonization of the urinary tract. Because urinary Cu levels are amenable to modulation, augmentation of the Cu-based host defense against UTI represents a novel approach to limiting bacterial colonization during UTI. KEYWORDS UTI, urinary tract infection, uropathogenic E. coli, UPEC, copper, ceruloplasmin U rinary tract infection (UTI) is an extremely common infectious disease in the UnitedStates and around the world (1, 2). In the United States alone, UTI leads to 11 million physician visits, 1.7 million emergency room visits, and 470,000 hospitalizations annually, with a direct cost of $3.5 billion (2). Infection of the urinary bladder (cystitis) is the most common form of UTI, whereas kidney infection (pyelonephritis), bacteremia, and sepsis are less common but more serious outcomes of UTI (3, 4). Women are four times as likely to develop UTI as men are because of anatomic differences (4). Children, the elderly, and individuals with catheters, anatomic and physiologic abnormalities of the urinary tract, uroliths, or diabetes mellitus are also highly susceptible to UTI (4).Uropathogenic Escherichia coli (UPEC) is the etiological agent in ϳ85% of the cystitis cases in otherwise healthy people (3). Free-living, adherent, biofilm, and intracellular forms of UPEC are found in the urinary bladder (5, 6). UPEC utilizes multiple virulence factors, including type 1 fimbriae, P fimbriae, flagella, toxins, and iron acquisition systems, to cause UTI (2, 7). In addition to UPEC, Klebsiella pneumoniae and Proteus

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α–Intercalated cells defend the urinary system from bacterial infection

Cited by 129 publications

References 117 publications

Predictive ability of NGAL in identifying urinary tract infection in children with neurogenic bladders

Predictive ability of NGAL in identifying urinary tract infection in children with neurogenic bladders

The nature of immune responses to urinary tract infections

Copper Is a Host Effector Mobilized to Urine during Urinary Tract Infection To Impair Bacterial Colonization

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