scholarly journals Apical localization of ITPK1 enhances its ability to be a modifier gene product in a murine tracheal cell model of cystic fibrosis

2006 ◽  
Vol 119 (7) ◽  
pp. 1320-1328 ◽  
Author(s):  
L. Yang
Keyword(s):  
Cystic Fibrosis ◽  
Gene Product ◽  
Cell Model ◽  
Modifier Gene ◽  
Tracheal Cell ◽  
Apical Localization

scholarly journals Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease

Nature ◽  
2009 ◽  
Vol 458 (7241) ◽  
pp. 1039-1042 ◽  
Author(s):  
YuanYuan Gu ◽  
Isaac T. W. Harley ◽  
Lindsay B. Henderson ◽  
Bruce J. Aronow ◽  
Ilja Vietor ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Modifier Gene ◽  
Cystic Fibrosis Lung ◽  
Cystic Fibrosis Lung Disease

scholarly journals TLR5 as an Anti-Inflammatory Target and Modifier Gene in Cystic Fibrosis

2010 ◽  
Vol 185 (12) ◽  
pp. 7731-7738 ◽  
Author(s):  
Christoph J. Blohmke ◽  
Julie Park ◽  
Aaron F. Hirschfeld ◽  
Rachel E. Victor ◽  
Julia Schneiderman ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Modifier Gene ◽  
Anti Inflammatory

scholarly journals Immunocytochemical localization of the cystic fibrosis gene product CFTR.

1991 ◽  
Vol 88 (20) ◽  
pp. 9262-9266 ◽  
Author(s):  
I. Crawford ◽  
P. C. Maloney ◽  
P. L. Zeitlin ◽  
W. B. Guggino ◽  
S. C. Hyde ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gene Product ◽  
Cystic Fibrosis Gene ◽  
Immunocytochemical Localization

scholarly journals Non-hierarchical, RhlR-regulated acyl-homoserine lactone quorum sensing in a cystic fibrosis isolate of Pseudomonas aeruginosa

2019 ◽  
Author(s):  
Renae L. Cruz ◽  
Kyle L. Asfahl ◽  
Sara Van den Bossche ◽  
Tom Coenye ◽  
Aurélie Crabbé ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Chronic Infection ◽  
Cell Model ◽  
Lung Epithelium ◽  
Independent Manner ◽  
Epithelium Cell ◽  
Regulated Gene Expression

ABSTRACTThe opportunistic pathogen Pseudomonas aeruginosa is a leading cause of airway infection in cystic fibrosis (CF) patients. P. aeruginosa employs several hierarchically arranged and interconnected quorum sensing (QS) regulatory circuits to produce a battery of virulence factors such as elastase, phenazines, and rhamnolipids. The QS transcription factor LasR sits atop this hierarchy, and activates the transcription of dozens of genes, including that encoding the QS regulator RhlR. Paradoxically, inactivating lasR mutations are frequently observed in isolates from CF patients with chronic P. aeruginosa infections. In contrast, mutations in rhlR are rare. We have recently shown that in CF isolates, the QS circuitry is often “rewired” such that RhlR acts in a LasR-independent manner. To begin understanding how QS activity differs in this “rewired” background, we characterized QS activation and RhlR-regulated gene expression in P. aeruginosa E90, a LasR-null, RhlR-active chronic infection isolate. In this isolate, RhlR activates the expression of 53 genes in response to increasing cell density. The genes regulated by RhlR include several that encode virulence factors. Some, but not all, of these genes are present in the QS regulon described in the well-studied laboratory strain PAO1. We also demonstrate that E90 produces virulence factors at similar concentrations to that of PAO1. Unlike PAO1, cytotoxicity by E90 in a three-dimensional lung epithelium cell model is also RhlR-regulated. These data illuminate a “rewired” LasR-independent RhlR regulon in chronic infection isolates and suggest that RhlR may be a target for therapeutic development in chronic infections.AUTHOR SUMMARYPseudomonas aeruginosa is a prominent cystic fibrosis (CF) pathogen that uses quorum sensing (QS) to regulate virulence. In laboratory strains, the key QS regulator is LasR. Some isolates from patients with chronic CF infections appear to use an alternate QS circuitry in which another transcriptional regulator, RhlR, mediates QS. We show that a LasR-null CF clinical isolate engages in QS through RhlR and remains capable of inducing cell death in an in vivo-like lung epithelium cell model. Our findings support the notion that LasR-null clinical isolates can engage in RhlR QS and highlight the centrality of RhlR gene regulation in chronic P. aeruginosa infections.

scholarly journals RhlR-Regulated Acyl-Homoserine Lactone Quorum Sensing in a Cystic Fibrosis Isolate of Pseudomonas aeruginosa

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Renae L. Cruz ◽  
Kyle L. Asfahl ◽  
Sara Van den Bossche ◽  
Tom Coenye ◽  
Aurélie Crabbé ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Chronic Infection ◽  
Cell Model ◽  
Lung Epithelium ◽  
Content Type ◽  
Epithelium Cell ◽  
Regulated Gene Expression

ABSTRACT The opportunistic pathogen Pseudomonas aeruginosa is a leading cause of airway infection in cystic fibrosis (CF) patients. P. aeruginosa employs several hierarchically arranged and interconnected quorum sensing (QS) regulatory circuits to produce a battery of virulence factors such as elastase, phenazines, and rhamnolipids. The QS transcription factor LasR sits atop this hierarchy and activates the transcription of dozens of genes, including that encoding the QS regulator RhlR. Paradoxically, inactivating lasR mutations are frequently observed in isolates from CF patients with chronic P. aeruginosa infections. In contrast, mutations in rhlR are rare. We have recently shown that in CF isolates, the QS circuitry is often rewired such that RhlR acts in a LasR-independent manner. To begin understanding how QS activity differs in this rewired background, we characterized QS activation and RhlR-regulated gene expression in P. aeruginosa E90, a LasR-null, RhlR-active chronic infection isolate. In this isolate, RhlR activates the expression of 53 genes in response to increasing cell density. The genes regulated by RhlR include several that encode virulence factors. Some, but not all, of these genes are present in the QS regulon described in the well-studied laboratory strain PAO1. We also demonstrate that E90 produces virulence factors at similar concentrations as PAO1, and in E90, RhlR plays a significant role in mediating cytotoxicity in a three-dimensional lung epithelium cell model. These data illuminate a rewired LasR-independent RhlR regulon in chronic infection isolates and suggest further investigation of RhlR as a possible target for therapeutic development in chronic infections. IMPORTANCE Pseudomonas aeruginosa is a prominent cystic fibrosis (CF) pathogen that uses quorum sensing (QS) to regulate virulence. In laboratory strains, the key QS regulator is LasR. Many isolates from patients with chronic CF infections appear to use an alternate QS circuitry in which another transcriptional regulator, RhlR, mediates QS. We show that a LasR-null CF clinical isolate engages in QS through RhlR and remains capable of inducing cell death in an in vivo-like lung epithelium cell model. Our findings support the notion that LasR-null clinical isolates can engage in RhlR QS and highlight the centrality of RhlR in chronic P. aeruginosa infections.

scholarly journals Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results

2009 ◽  
Vol 126 (6) ◽  
pp. 763-778 ◽  
Author(s):  
Ruslan Dorfman ◽  
Weili Li ◽  
Lei Sun ◽  
Fan Lin ◽  
Yongqian Wang ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Gene Mapping ◽  
Modifier Gene ◽  
Meconium Ileus ◽  
Gene Study

scholarly journals Consistent Assignment of Risk and Benign Allele at rs2303153 in the CF Modifier Gene SCNN1B in Three Independent F508del-CFTR Homozygous Patient Populations

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1554
Author(s):  
Frauke Stanke ◽  
Tim Becker ◽  
Haide Susanne Ismer ◽  
Inga Dunsche ◽  
Silke Hedtfeld ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Risk Allele ◽  
Association Studies ◽  
Regulatory Element ◽  
Genetic Modifier ◽  
Modifier Gene ◽  
Intestinal Epithelia ◽  
Transepithelial Sodium Transport ◽  
Homozygous Patient

CFTR encodes for a chloride and bicarbonate channel expressed at the apical membrane of polarized epithelial cells. Transepithelial sodium transport mediated by the amiloride-sensitive sodium channel ENaC is thought to contribute to the manifestation of CF disease. Thus, ENaC is a therapeutic target in CF and a valid cystic fibrosis modifier gene. We have characterized SCNN1B as a genetic modifier in the three independent patient cohorts of F508del-CFTR homozygotes. We could identify a regulatory element at SCNN1B to the genomic segment rs168748-rs2303153-rs4968000 by fine-mapping (Pbest = 0.0177), consistently observing the risk allele rs2303153-C and the contrasting benign allele rs2303153-G in all three patient cohorts. Furthermore, our results show that expression levels of SCNN1B are associated with rs2303153 genotype in intestinal epithelia (P = 0.003). Our data confirm that the well-established biological role of SCNN1B can be recognized by an association study on informative endophenotypes in the rare disease cystic fibrosis and calls attention to reproducible results in association studies obtained from small, albeit carefully characterized patient populations.

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