Role of lung iron in determining the bacterial and host struggle in cystic fibrosis

2009 ◽  
Vol 297 (5) ◽  
pp. L795-L802 ◽  
Author(s):  
D. W. Reid ◽  
G. J. Anderson ◽  
I. L. Lamont
Keyword(s):  
Cystic Fibrosis ◽  
Iron Homeostasis ◽  
Iron Acquisition ◽  
Genetic Disorder ◽  
Bacterial Species ◽  
System Disease ◽  
Liver And Pancreas ◽  
Pseudomonas Aeruginosa Infection ◽  
The Relationship

Cystic fibrosis (CF) is the most common lethal genetic disorder in Caucasian populations. It is a multiorgan system disease that affects the lungs, gastrointestinal tract, liver, and pancreas. The majority of morbidity and mortality in CF relates to chronic airway infection with a variety of bacterial species, commencing in very early infancy, which results in lung destruction and ultimately organ failure ( 41 , 43 ). This review focuses on iron homeostasis in the CF lung and its role in determining the success and chronicity of Pseudomonas aeruginosa infection. There have been previous excellent reviews regarding iron metabolism in the lower respiratory tract and mechanisms of P. aeruginosa iron acquisition, and we direct readers to these articles for further background reading ( 31 , 53 , 58 , 77 , 96 ). In this review, we have brought the “two sides of the coin” together to provide a holistic overview of the relationship between host and bacterial iron homeostasis and put this information into the context of current understanding on infection in the CF lung.

scholarly journals Inflammation in the lungs of patients diagnosed with Cystic Fibrosis: Association with iron deficiency

SURG Journal ◽  
1969 ◽  
Vol 2 (1) ◽  
pp. 3-10
Author(s):  
Dawn Armstrong ◽  
Lindsay Robinson
Keyword(s):  
Cystic Fibrosis ◽  
Iron Deficiency ◽  
Inflammatory Cytokines ◽  
Wide Spectrum ◽  
Iron Status ◽  
Tissue Destruction ◽  
Hypoxic Conditions ◽  
Mediators Of Inflammation ◽  
The Relationship

Cystic Fibrosis (CF) is characterized by a wide spectrum of phenotypic characteristics such as; deep coughing, increased mucous production, and weight loss. However, only recently was the role of inflammation on the etiology of the disease recognized. CF is characterized as a cyclic progression of infective exacerbations and stable periods initiated by the presence of Pseudomonas Aeruginosa (PA). An increase in inflammatory cytokines/mediators and a decrease in anti-inflammatory cytokines contribute to the net inflammation and overall tissue destruction of the lungs. PA is associated with the low iron status that is seen in 60-75% of the CF population, through the presence of iron sequestering siderophores which distract iron from the tissues. Iron deficiency (ID) initiates further symptoms such as; fatigue, tachycardia, weakness, brittle nails etc, in addition to those caused by CF. The colonization of PA may be the cause or a result of increased iron (ferritin) concentrations in the lungs, but independent of the original relationship, results in a decreased iron status. Iron is used by PA under hypoxic conditions such as in the fibrosis lung, as a source of energy. Studies on the relationship between CF and ID contribute a variety of possible causes although currently no direct connection has been discovered. At this stage, further studies in this area are needed. This review will primarily focus on the affects of CF on iron status in humans, and secondarily examine the effect of mediators of inflammation in respects to ID.

scholarly journals The Regulator PerR Is Involved in Oxidative Stress Response and Iron Homeostasis and Is Necessary for Full Virulence of Streptococcus pyogenes

2002 ◽  
Vol 70 (9) ◽  
pp. 4968-4976 ◽  
Author(s):  
Susanna Ricci ◽  
Robert Janulczyk ◽  
Lars Björck
Keyword(s):  
Oxidative Stress ◽  
Streptococcus Pyogenes ◽  
Stress Responses ◽  
Metal Binding ◽  
Iron Homeostasis ◽  
Bacterial Species ◽  
Transcriptional Analysis ◽  
Wild Type ◽  
Allelic Replacement

ABSTRACT Ferric uptake regulator (Fur) and Fur-like proteins form an important family of transcriptional regulators in many bacterial species. In this work we have characterized a Fur-like protein, the peroxide regulator PerR, in an M1 serotype of Streptococcus pyogenes. To determine the role of PerR in S. pyogenes, we inactivated the gene by allelic replacement. PerR-deficient bacteria showed 48% reduction of 55Fe incorporation from the culture medium. Transcriptional analysis revealed that mtsA, encoding a metal-binding protein of an ABC transporter in S. pyogenes, was transcribed at lower levels than were wild-type cells. Although total iron accumulation was reduced, the growth of the mutant strain was not significantly hampered. The mutant showed hyperresistance to hydrogen peroxide, and this response was induced in wild-type cells by growth in aerobiosis, suggesting that PerR acts as an oxidative stress-responsive repressor. PerR may also participate in the response to superoxide stress, as the perR mutant was more sensitive to the superoxide anion and had a reduced transcription of sodA, which encodes the sole superoxide dismutase of S. pyogenes. Complementation of the mutation with a functional perR gene restored 55Fe incorporation, response to peroxide stress, and transcription of both mtsA and sodA to levels comparable to those of wild-type bacteria. Finally, the perR mutant was attenuated in virulence in a murine air sac model of infection (P < 0.05). These results demonstrate that PerR is involved in the regulation of iron homeostasis and oxidative stress responses and that it contributes to the virulence of S. pyogenes.

scholarly journals Modulation of Gut Microbiota to Enhance Effect of Checkpoint Inhibitor Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Jianmin Wu ◽  
Shan Wang ◽  
Bo Zheng ◽  
Xinyao Qiu ◽  
Hongyang Wang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Therapeutic Strategy ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Bacterial Species ◽  
Treatment Needs ◽  
Treatment Complication ◽  
Checkpoint Inhibitor Therapy ◽  
The Relationship

Accumulating evidence demonstrated the crucial role of gut microbiota in many human diseases, including cancer. Checkpoint inhibitor therapy has emerged as a novel treatment and has been clinically accepted as a major therapeutic strategy for cancer. Gut microbiota is related to cancer and the effect of immune checkpoint inhibitors (ICIs), and supplement with specific bacterial species can restore or enhance the responses to the ICIs. Namely, specified bacteria can serve as the biomarkers for distinguishing the patient who will respond to ICIs and determine the effectiveness of ICIs, as well as predicting the efficacy of checkpoint inhibitor immunotherapy. Regardless of the significant findings, the relationship between gut microbiota and the effect of ICIs treatment needs a more thorough understanding to provide more effective therapeutic plans and reduce treatment complication. In this review, we summarized the role of gut microbiota played in immune system and cancer. We mainly focus on the relationship between gut microbiota and the checkpoint inhibitor immunotherapy.

scholarly journals Transcriptional Response of Leptospira interrogans to Iron Limitation and Characterization of a PerR Homolog

2010 ◽  
Vol 78 (11) ◽  
pp. 4850-4859 ◽  
Author(s):  
Miranda Lo ◽  
Gerald L. Murray ◽  
Chen Ai Khoo ◽  
David A. Haake ◽  
Richard L. Zuerner ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Iron Homeostasis ◽  
Storage Proteins ◽  
Iron Acquisition ◽  
Bacterial Species ◽  
Transcriptional Response ◽  
Oxidative Stress Response ◽  
Wild Type ◽  
In The Wild

ABSTRACT Leptospirosis is a globally significant zoonosis caused by Leptospira spp. Iron is essential for growth of most bacterial species. Since iron availability is low in the host, pathogens have evolved complex iron acquisition mechanisms to survive and establish infection. In many bacteria, expression of iron uptake and storage proteins is regulated by Fur. L. interrogans encodes four predicted Fur homologs; we have constructed a mutation in one of these, la1857. We conducted microarray analysis to identify iron-responsive genes and to study the effects of la1857 mutation on gene expression. Under iron-limiting conditions, 43 genes were upregulated and 49 genes were downregulated in the wild type. Genes encoding proteins with predicted involvement in inorganic ion transport and metabolism (including TonB-dependent proteins and outer membrane transport proteins) were overrepresented in the upregulated list, while 54% of differentially expressed genes had no known function. There were 16 upregulated genes of unknown function which are absent from the saprophyte L. biflexa and which therefore may encode virulence-associated factors. Expression of iron-responsive genes was not significantly affected by mutagenesis of la1857, indicating that LA1857 is not a global regulator of iron homeostasis. Upregulation of heme biosynthetic genes and a putative catalase in the mutant suggested that LA1857 is more similar to PerR, a regulator of the oxidative stress response. Indeed, the la1857 mutant was more resistant to peroxide stress than the wild type. Our results provide insights into the role of iron in leptospiral metabolism and regulation of the oxidative stress response, including genes likely to be important for virulence.

Molecular mechanisms of iron uptake in eukaryotes

1996 ◽  
Vol 76 (1) ◽  
pp. 31-47 ◽  
Author(s):  
D. M. de Silva ◽  
C. C. Askwith ◽  
J. Kaplan
Keyword(s):  
Iron Uptake ◽  
Mammalian Cells ◽  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Iron Acquisition ◽  
Genetic Disorders ◽  
Essential Element ◽  
Recent Developments

Iron serves essential functions in both prokaryotes and eukaryotes, and cells have highly specialized mechanisms for acquiring and handling this metal. The primary mechanism by which the concentration of iron in biologic systems is controlled is through the regulation of iron uptake. Although the role of transferrin in mammalian iron homeostasis has been well characterized, the study of genetic disorders of iron metabolism has revealed other, transferrin-independent, mechanisms by which cells can acquire iron. In an attempt to understand how eukaryotic systems take up this essential element, investigators have begun studying the simple eukaryote Saccharomyces cerevisiae. Several genes have been identified and cloned that act in concert to allow iron acquisition from the environment. Some of these genes appear to have functional homologues in human systems. This review focuses on the recent developments in understanding eukaryotic iron uptake with an emphasis on the genetic and molecular characterization of these systems in both cultured mammalian cells and S. cerevisiae. An unexpected connection between iron and copper homeostasis has been revealed by recent genetic studies, which confirm biologic observations made several decades ago.

scholarly journals Inflammatory Markers in Cystic Fibrosis Patients with LungPseudomonas AeruginosaInfection

1999 ◽  
Vol 8 (3) ◽  
pp. 159-167 ◽  
Author(s):  
A. L. Pukhalsky ◽  
N. I. Kapranov ◽  
E. A. Kalashnikova ◽  
G. V. Shmarina ◽  
L. A. Shabalova ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Antibiotic Treatment ◽  
Inflammatory Markers ◽  
Chloride Channels ◽  
Genetic Disorder ◽  
Peripheral Blood Lymphocytes ◽  
Tnf Α ◽  
Elevated Activity ◽  
The Relationship ◽  
Immunomodulating Drugs

Chronic endobronchial inflammation and bacterial infection are the main causes of morbidity and mortality in cystic fibrosis (CF), an autosomal recessive genetic disorder associated with improper function of chloride channels. Inflammation in CF lung is greatly amplified afterPseudomonas aeruginosainfection. In this study the relationship betweenP. aeruginosastatus and inflammatory markers has been investigated. Seventeen CF children in acute lung exacerbation were examined. CF patients withoutP. aeruginosainfection were characterized by elevated activity of sputum elastase, reduced response of peripheral blood lymphocytes to PHA and significant resistance to the antiproliferative action of glucocorticoids. These parameters were normalized after antibiotic treatment. The patients with prolongedP. aeruginosainfection demonstrated extremely high levels of elastase activity and elevated amounts of sputum IL-8 and TNF-α. Although antibiotic treatment resulted in clinical improvement, it failed to suppress excessive immune response in the lung. The data indicate that CF patients with prolongedP. aeruginosaneed the modified treatment, which should include immunomodulating drugs and protease inhibitors as well as antibacterial therapy.

scholarly journals Iron and Fur Regulation in Vibrio cholerae and the Role of Fur in Virulence

2005 ◽  
Vol 73 (12) ◽  
pp. 8167-8178 ◽  
Author(s):  
Alexandra R. Mey ◽  
Elizabeth E. Wyckoff ◽  
Vanamala Kanukurthy ◽  
Carolyn R. Fisher ◽  
Shelley M. Payne
Keyword(s):  
Gene Expression ◽  
Vibrio Cholerae ◽  
Iron Acquisition ◽  
Bacterial Species ◽  
Regulation Of Gene Expression ◽  
Transport Systems ◽  
Infant Mouse ◽  
Genes Encoding ◽  
Regulatory Functions

ABSTRACT Regulation of iron uptake and utilization is critical for bacterial growth and for prevention of iron toxicity. In many bacterial species, this regulation depends on the iron-responsive master regulator Fur. In this study we report the effects of iron and Fur on gene expression in Vibrio cholerae. We show that Fur has both positive and negative regulatory functions, and we demonstrate Fur-independent regulation of gene expression by iron. Nearly all of the known iron acquisition genes were repressed by Fur under iron-replete conditions. In addition, genes for two newly identified iron transport systems, Feo and Fbp, were found to be negatively regulated by iron and Fur. Other genes identified in this study as being induced in low iron and in the fur mutant include those encoding superoxide dismutase (sodA), fumarate dehydratase (fumC), bacterioferritin (bfr), bacterioferritin-associated ferredoxin (bfd), and multiple genes of unknown function. Several genes encoding iron-containing proteins were repressed in low iron and in the fur mutant, possibly reflecting the need to reserve available iron for the most critical functions. Also repressed in the fur mutant, but independently of iron, were genes located in the V. cholerae pathogenicity island, encoding the toxin-coregulated pilus (TCP), and genes within the V. cholerae mega-integron. The fur mutant exhibited very weak autoagglutination, indicating a possible defect in expression or assembly of the TCP, a major virulence factor of V. cholerae. Consistent with this observation, the fur mutant competed poorly with its wild-type parental strain for colonization of the infant mouse gut.

scholarly journals Role of Porins in Iron Uptake by Mycobacterium smegmatis

2010 ◽  
Vol 192 (24) ◽  
pp. 6411-6417 ◽  
Author(s):  
Christopher M. Jones ◽  
Michael Niederweis
Keyword(s):  
Outer Membrane ◽  
Mycobacterium Smegmatis ◽  
Iron Homeostasis ◽  
Iron Acquisition ◽  
Gram Negative Bacteria ◽  
Ferric Ions ◽  
Intracellular Iron ◽  
High Iron ◽  
Hydrophilic Solutes

ABSTRACT Many bacteria rely on siderophores to extract iron from the environment. However, acquisition of iron-loaded siderophores is dependent on high-affinity uptake systems that are not produced under high-iron conditions. The fact that bacteria are able to maintain iron homeostasis in the absence of siderophores indicates that alternative iron acquisition systems exist. It has been speculated that such low-affinity uptake of iron in Gram-negative bacteria includes diffusion of iron ions or chelates across the outer membrane through porins. The outer membrane of the saprophytic Mycobacterium smegmatis contains the Msp family of porins, which enable the diffusion of small and hydrophilic solutes, such as monosaccharides, amino acids, and phosphate. However, it is unknown how cations cross the outer membrane of mycobacteria. Here, we show that the Msp porins of M. smegmatis are involved in the acquisition of soluble iron under high-iron conditions. Uptake of ferric ions by a triple porin mutant was reduced compared to wild-type (wt) M. smegmatis. An intracellular iron reporter indicated that derepression of iron-responsive genes occurs at higher iron concentrations in the porin mutant. This was consistent with the finding that the porin mutant produced more siderophores under low-iron conditions than wt M. smegmatis. In contrast, uptake of the exochelin MS, the main siderophore of M. smegmatis, was not affected by the lack of porins, indicating that a specific outer membrane siderophore receptor exists. These results provide, to our knowledge, the first experimental evidence that general porins are indeed the outer membrane conduit of low-affinity iron acquisition systems in bacteria.

Impaired TLR4 and HIF expression in cystic fibrosis bronchial epithelial cells downregulates hemeoxygenase-1 and alters iron homeostasis in vitro

2014 ◽  
Vol 307 (10) ◽  
pp. L791-L799 ◽  
Author(s):  
Shashi Chillappagari ◽  
Shalini Venkatesan ◽  
Virajith Garapati ◽  
Poornima Mahavadi ◽  
Antje Munder ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Iron Homeostasis ◽  
Hypoxia Inducible Factor ◽  
Immunohistochemical Analysis ◽  
Surface Expression ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Intracellular Iron

Hemeoxygenase-1 (HO-1), an inducible heat shock protein, is upregulated in response to multiple cellular insults via oxidative stress, lipopolysaccharides (LPS), and hypoxia. In this study, we investigated in vitro the role of Toll-like receptor 4 (TLR4), hypoxia-inducible factor 1α (HIF-1α), and iron on HO-1 expression in cystic fibrosis (CF). Immunohistochemical analysis of TLR4, HO-1, ferritin, and HIF-1α were performed on lung sections of CFTR−/− and wild-type mice. CFBE41o- and 16HBE14o- cell lines were employed for in vitro analysis via immunoblotting, immunofluorescence, real-time PCR, luciferase reporter gene analysis, and iron quantification. We observed a reduced TLR4, HIF-1α, HO-1, and ferritin in CFBE41o- cell line and CF mice. Knockdown studies using TLR4-siRNA in 16HBE14o- revealed significant decrease of HO-1, confirming the role of TLR4 in HO-1 downregulation. Inhibition of HO-1 using tin protoporphyrin in 16HBE14o- cells resulted in increased iron levels, suggesting a probable role of HO-1 in iron accumulation. Additionally, sequestration of excess iron using iron chelators resulted in increased hypoxia response element response in CFBE41o- and 16HBE14o-, implicating a role of iron in HIF-1α stabilization and HO-1. To conclude, our in vitro results demonstrate that multiple regulatory factors, such as impaired TLR4 surface expression, increased intracellular iron, and decreased HIF-1α, downregulate HO-1 expression in CFBE41o- cells.

scholarly journals Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis

2018 ◽  
Vol 51 (3) ◽  
pp. 1701910 ◽  
Author(s):  
A. Susanne Dittrich ◽  
Iris Kühbandner ◽  
Stefanie Gehrig ◽  
Verena Rickert-Zacharias ◽  
Matthew Twigg ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Forced Expiratory Volume ◽  
Healthy Controls ◽  
Elastase Activity ◽  
Residual Capacity ◽  
The Relationship

Neutrophil elastase (NE) is a key risk factor for severity of cystic fibrosis (CF) lung disease. Recent studies identified increased NE activity on the surface of airway neutrophils from CF-like mice and patients with CF. However, the role of surface-bound NE in CF lung disease remains unknown. We determined the relationship between surface-bound NE activity and severity of lung disease in CF.Surface-bound NE activity was measured on sputum neutrophils from 35 CF patients and eight healthy controls using novel lipidated Förster resonance energy transfer reporters and correlated with free NE activity, neutrophil counts, interleukin-8, myeloperoxidase and antiproteases in sputum supernatant, and with lung function parameters.Surface-bound NE activity was increased in CF compared to healthy controls (p<0.01) and correlated with free NE activity (p<0.05) and other inflammation markers (p<0.001). Surface-bound and free NE activity correlated with forced expiratory volume in 1 s % predicted (p<0.01 and p<0.05), but only surface-bound NE activity correlated with plethysmographic functional residual capacity % pred (p<0.01) in patients with CF.We demonstrate that surface-bound NE activity on airway neutrophils correlates with severity of lung disease in patients with CF. Our results suggest that surface-bound NE activity may play an important role in the pathogenesis and serve as novel biomarker in CF lung disease.

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