Altered terminal glycosylation and the pathophysiology of CF lung disease

Rhim, Andrew D.; Stoykova, Lidia I.; Trindade, Arvind J.; Glick, Mary Catherine; Scanlin, Thomas F.

doi:10.1016/j.jcf.2004.05.021

Cited by 21 publications

(18 citation statements)

References 7 publications

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“…A female patient with cystic fibrosis showed high %CDT as well as a type 2 Tf-IEF profile, supporting the hypothesis that altered function of cystic fibrosis transmembrane conductance regulator (CFTR) affects the compartmentalization of glycosyltransferases in the Golgi, thereby disturbing protein glycosylation (39 ). Moreover, we have found several types of Tf polymorphisms that hampered efforts to reach a conclusive diagnosis in sick children.…”

Section: Discussionmentioning

confidence: 52%

Screening Using Serum Percentage of Carbohydrate-Deficient Transferrin for Congenital Disorders of Glycosylation in Children with Suspected Metabolic Disease

et al. 2008

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BACKGROUND:Diagnoses of congenital disorders of glycosylation (CDG) are based on clinical suspicion and analysis of transferrin (Tf) isoforms. Here we present our experience of CDG screening in children with a suspected metabolic disease by determination of serum percentage of carbohydrate-deficient transferrin (%CDT) in tandem with isoelectric focusing (IEF) analysis of Tf and ␣ 1 -antitrypsin (␣ 1 -AT).

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Section: Discussionmentioning

confidence: 52%

Screening Using Serum Percentage of Carbohydrate-Deficient Transferrin for Congenital Disorders of Glycosylation in Children with Suspected Metabolic Disease

et al. 2008

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“…CFTR itself is a highly glycosylated protein, and there are published data that suggest that the sugar composition of membrane glycoproteins and secreted mucins is altered in CF, though the exact mechanism remains unknown (45). We are currently testing whether N-glycosylation or HSPGs are upregulated in lung tissues from patients with CF.…”

Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosa -Mediated Damage Requires Distinct Receptors at the Apical and Basolateral Surfaces of the Polarized Epithelium

2010

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Pseudomonas aeruginosa, an important opportunistic pathogen of humans, exploits epithelial damage to establish infection. We have rigorously explored the role of N-glycoproteins and heparan sulfate proteoglycans (HSPGs) in P. aeruginosa-mediated attachment and subsequent downstream events at the apical (AP) and basolateral (BL) surfaces of polarized epithelium. We demonstrate that the N-glycan chains at the AP surface are necessary and sufficient for binding, invasion, and cytotoxicity to kidney (MDCK) and airway (Calu-3) cells grown at various states of polarization on Transwell filters. Upregulation of N-glycosylation enhanced binding, whereas pharmacologic inhibition of N-glycosylation or infection of MDCK cells defective in N-glycosylation resulted in decreased binding. In contrast, at the BL surface, the HS moiety of HSPGs mediated P. aeruginosa binding, cytotoxicity, and invasion. In incompletely polarized epithelium, HSPG abundance was increased at the AP surface, explaining its increased susceptibility to P. aeruginosa colonization and damage. Using MDCK cells grown as three-dimensional cysts as a model for epithelial organs, we show that P. aeruginosa specifically colocalized with HS-rich areas at the BL membrane but with complex N-glycans at the AP surface. Finally, P. aeruginosa bound to HS chains and N-glycans coated on plastic surfaces, showing the highest binding affinity toward isolated HS chains. Together, these findings demonstrate that P. aeruginosa recognizes distinct receptors on the AP and BL surfaces of polarized epithelium. Changes in the composition of N-glycan chains and/or in the distribution of HSPGs may explain the enhanced susceptibility of damaged epithelium to P. aeruginosa.Ninety-five percent of all infectious agents enter through mucosal surfaces of the gastrointestinal, genitourinary, and respiratory tracts (reviewed in reference 35). These mucosal surfaces are usually lined by a single layer of epithelial cells, which serves as the primary barrier against the entry of most infectious agents and can be considered a primary component of the innate immune system. Epithelial cells form highly polarized cell layers with apical (AP) and basolateral (BL) surfaces that exhibit distinct protein, lipid, and glycoconjugate compositions. Pseudomonas aeruginosa is a ubiquitous opportunistic pathogen of humans that exploits injured mucosa to cause acute and chronic infections with high morbidity and mortality (reviewed in references 26 and 31). In the setting of epithelial injury and immunocompromise, this Gram-negative pathogen causes serious infections in patients with extensive burns, corneal trauma, or catheter-related bladder injury or in those on ventilators. In addition, P. aeruginosa chronically colonizes the lungs of patients with cystic fibrosis (CF) (4), leading to severe pulmonary damage and death. Despite aggressive antibiotic therapy, the fatality rate for many P. aeruginosa infections is 40%, and new approaches to treatment are even more critical now that antibiotic resistance...

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“…In studies of Stable Isotope Labeling with Amino acids in Cell culture (SILAC) for profiling of pancreatic cancer cell secretomes, 145 differentially expressed proteins infrequently correlate with mRNA analysis [49,103]. Moreover, function(s) of proteins will depend on post-translational modifications [26,102,112]. Microarrays are also limited as they only detect known sequences included within any given array and the actual detection system may be limited by either falling below the level of detection or by presenting a saturating signal [130].…”

Section: Genomics and Proteomics: A Means To De-termine Fingerprints mentioning

confidence: 99%

Human Immunodeficiency Virus-Mononuclear Phagocyte Interactions:Emerging Avenues of Biomarker Discovery, Modes of Viral Persistence and Disease Pathogenesis

Ciborowski

Gendelman²

2006

CHR

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Mononuclear phagocytes (MP; bone marrow monocyte-derived macrophages, histiocytes, alveolar macrophages, Kupffer cells, perivascular macrophages, and microglia) function as sentry and surveillance cells by acting as debris scavengers, killers of microbial pathogens, and regulators of immune responses. Interestingly, these same cells are reservoirs and vehicles of dissemination for the human immunodeficiency virus (HIV). How virus alters the MP immunoregulatory activities so it can complete its own life cycle and affect disease is only recently being unravelled. Physiologic, anatomic and functional changes also underlie virus-MP interactions and include multinucleated giant cell formation, changes in ion channel expression and cell volume, and robust secretory responses with the production of numerous secretory factors affecting tissue injury. The balance between such MP activities and ability to both mobilize an adaptive immune response to thwart viral growth underlies the progression of viral infection and clinical disease. This review serves to discuss the functions of MP in HIV disease by bringing together what is known with what remains unknown. The advent of functional genomics and proteomics has opened the ways to address the intricacies of viral-host interactions and has provided new avenues for therapeutic interventions and disease monitoring that takes advantage of specific intracellular relationships between the virus and its host cell.

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Altered terminal glycosylation and the pathophysiology of CF lung disease

Cited by 21 publications

References 7 publications

Screening Using Serum Percentage of Carbohydrate-Deficient Transferrin for Congenital Disorders of Glycosylation in Children with Suspected Metabolic Disease

Screening Using Serum Percentage of Carbohydrate-Deficient Transferrin for Congenital Disorders of Glycosylation in Children with Suspected Metabolic Disease

Pseudomonas aeruginosa -Mediated Damage Requires Distinct Receptors at the Apical and Basolateral Surfaces of the Polarized Epithelium

Human Immunodeficiency Virus-Mononuclear Phagocyte Interactions:Emerging Avenues of Biomarker Discovery, Modes of Viral Persistence and Disease Pathogenesis

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