Airway iron and iron-regulatory cytokines in cystic fibrosis

Reid, David W.; Lam, Quynh; Schneider, Hans‐Gerhard; Walters, E. Haydn

doi:10.1183/09031936.04.00104803

Cited by 73 publications

(97 citation statements)

References 27 publications

(22 reference statements)

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“…The media was modified to include 3 mg ml À 1 ferritin as an alternate iron source to more appropriately reflect the conditions of the CF lung (Stites et al, 1998;Reid et al, 2004;Ghio et al, 2012;Hare et al, 2012). Other modifications included the absence of bovine serum albumin and an increase to 20 mg ml À 1 porcine stomach mucin to better reflect our experience with CF sputum consistency.…”

Section: Inoculation Of Wincf Systemmentioning

confidence: 99%

A Winogradsky-based culture system shows an association between microbial fermentation and cystic fibrosis exacerbation

et al. 2014

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There is a poor understanding of how the physiology of polymicrobial communities in cystic fibrosis (CF) lungs contributes to pulmonary exacerbations and lung function decline. In this study, a microbial culture system based on the principles of the Winogradsky column (WinCF system) was developed to study the physiology of CF microbes. The system used glass capillary tubes filled with artificial sputum medium to mimic a clogged airway bronchiole. Chemical indicators were added to observe microbial physiology within the tubes. Characterization of sputum samples from seven patients showed variation in pH, respiration, biofilm formation and gas production, indicating that the physiology of CF microbial communities varied among patients. Incubation of homogenized tissues from an explant CF lung mirrored responses of a Pseudomonas aeruginosa pure culture, supporting evidence that end-stage lungs are dominated by this pathogen. Longitudinal sputum samples taken through two exacerbation events in a single patient showed that a two-unit drop in pH and a 30% increase in gas production occurred in the tubes prior to exacerbation, which was reversed with antibiotic treatment. Microbial community profiles obtained through amplification and sequencing of the 16S rRNA gene showed that fermentative anaerobes became more abundant during exacerbation and were then reduced during treatment where P. aeruginosa became the dominant bacterium. Results from the WinCF experiments support the model where two functionally different CF microbial communities exist, the persistent Climax Community and the acute Attack Community. Fermentative anaerobes are hypothesized to be the core members of the Attack Community and production of acidic and gaseous products from fermentation may drive developing exacerbations. Treatment targeting the Attack Community may better resolve exacerbations and resulting lung damage.

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Section: Inoculation Of Wincf Systemmentioning

confidence: 99%

A Winogradsky-based culture system shows an association between microbial fermentation and cystic fibrosis exacerbation

et al. 2014

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“…Just such a scenario may apply during chronic infections in cystic fibrosis lungs, where pyoverdine-negative mutants typically accumulate over time [56][57][58]. One possible explanation for this observation is that siderophores are not required in the lung because iron concentration is increased (7.5 -33 mM; [59,60]). Alternatively, it has been suggested that selection against pyoverdine production occurs because of cheating (i.e.…”

Section: Discussionmentioning

confidence: 99%

Switching between apparently redundant iron-uptake mechanisms benefits bacteria in changeable environments

2013

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Bacteria often possess multiple siderophore-based iron uptake systems for scavenging this vital resource from their environment. However, some siderophores seem redundant, because they have limited iron-binding efficiency and are seldom expressed under iron limitation. Here, we investigate the conundrum of why selection does not eliminate this apparent redundancy. We focus on Pseudomonas aeruginosa, a bacterium that can produce two siderophores-the highly efficient but metabolically expensive pyoverdine, and the inefficient but metabolically cheap pyochelin. We found that the bacteria possess molecular mechanisms to phenotypically switch from mainly producing pyoverdine under severe iron limitation to mainly producing pyochelin when iron is only moderately limited. We further show that strains exclusively producing pyochelin grew significantly better than strains exclusively producing pyoverdine under moderate iron limitation, whereas the inverse was seen under severe iron limitation. This suggests that pyochelin is not redundant, but that switching between siderophore strategies might be beneficial to trade off efficiencies versus costs of siderophores. Indeed, simulations parameterized from our data confirmed that strains retaining the capacity to switch between siderophores significantly outcompeted strains defective for one or the other siderophore under fluctuating iron availabilities. Finally, we discuss how siderophore switching can be viewed as a form of collective decision-making, whereby a coordinated shift in behaviour at the group level emerges as a result of positive and negative feedback loops operating among individuals at the local scale.

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“…The E. coli fur mutant used in these studies can produce more than 100-fold more enterobactin than the parent strain when grown in vitro in iron-replete medium (3), conditions under which Salmonella enterica serovar Typhimurium fur mutants may produce more than 140 M enterobactin (42). Iron is virtually undetectable in respiratory secretions, such as sputum (30,36) or bronchialalveolar lavage (35), and free iron is thought to be as low as 10 Ϫ24 M in the serum (2). In contrast, the cell culture system employed for these studies contains supraphysiologic levels of iron (Յ2 ϫ 10 Ϫ6 M [personal communication from the manufacturer]).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-8 Secretion in Response to Aferric Enterobactin Is Potentiated by Siderocalin

Nelson¹,

Ratner²,

Barasch

et al. 2007

Infect Immun

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Siderophores are low-molecular-weight iron chelators secreted by microbes to obtain iron under deprivation. We hypothesized that the catecholate siderophore enterobactin, produced by Enterobacteriaceae, serves as a proinflammatory signal for respiratory epithelial cells. Respiratory tract responses were explored, since at this site siderocalin, an enterobactin-binding mammalian gene product, is expressed inducibly at high levels and enterobactin-secreting respiratory flora is rare, suggesting selection against a dependence on enterobactin. Addition of aferric, but not iron-saturated, enterobactin elicits a dose-dependent increase in secretion of the proinflammatory chemokine interleukin-8 by human respiratory epithelial cells in culture. This response to purified enterobactin is potentiated by recombinant siderocalin at physiologically relevant concentrations. Conditioned media from genetically modified Escherichia coli strains expressing various levels of enterobactin induce an enterobactin-mediated proinflammatory response. Siderocalin has been shown to deliver enterobactin to other mammalian cell types, exogenously supplied siderocalin can be detected within epithelial cells, and siderocalin increases delivery of enterobactin to the intracellular compartment. Although many siderophores perturb labile cellular iron pools, only enterobactin elicits interleukin-8 secretion, suggesting that iron chelation is necessary but not sufficient. Thus, aferric enterobactin may be a proinflammatory signal for respiratory epithelial cells, permitting detection of microbial communities that have disturbed local iron homeostasis, and siderocalin expression by the host amplifies this signal. This may be a novel mechanism for the mucosa to respond to metabolic signals of expanding microbial communities.

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Airway iron and iron-regulatory cytokines in cystic fibrosis

Cited by 73 publications

References 27 publications

A Winogradsky-based culture system shows an association between microbial fermentation and cystic fibrosis exacerbation

A Winogradsky-based culture system shows an association between microbial fermentation and cystic fibrosis exacerbation

Switching between apparently redundant iron-uptake mechanisms benefits bacteria in changeable environments

Interleukin-8 Secretion in Response to Aferric Enterobactin Is Potentiated by Siderocalin

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