Impaired Airway Epithelial Barrier Integrity in Response to Stenotrophomonas maltophilia Proteases, Novel Insights Using Cystic Fibrosis Bronchial Epithelial Cell Secretomics

Stenotrophomonas maltophilia is a Gram-negative opportunistic pathogen that can chronically colonize the lungs of people with cystic fibrosis (CF) and is associated with lethal pulmonary hemorrhage in immunocompromised patients. Its secreted virulence factors include the extracellular serine proteases StmPR1, StmPR2, and StmPR3. To explore the impact of secreted virulence determinants on pulmonary mucosal defenses in CF, we examined the secretome of human CFBE41o- bronchial epithelial cells in response to treatment with S. maltophilia K279a cell culture supernatant (CS) using a liquid-chromatography-tandem mass spectrometry (LC-MS/MS) based label-free quantitative (LFQ) shotgun proteomics approach for global profiling of the cell secretome. Secretome analysis identified upregulated pathways mainly relating to biological adhesion and epithelial cell signaling in infection, whereas no specific pathways relating to the immune response were enriched. Further exploration of the potentially harmful effects of K279a CS on CF bronchial epithelial cells, demonstrated that K279a CS caused CFBE41o- cell condensation and detachment, reversible by the serine protease inhibitor PMSF. K279a CS also decreased trans-epithelial electrical resistance in CFBE41o- cell monolayers suggestive of disruption of tight junction complexes (TJC). This finding was corroborated by an observed increase in fluorescein isothiocyanate (FITC) dextran permeability and by demonstrating PMSF-sensitive degradation ...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research

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There is an urgent need for new antimicrobials to treat the opportunistic Gram-negative Burkholderia cenocepacia, which represents a problematic challenge for cystic fibrosis patients. Recently, a benzothiadiazole derivative, C109, was shown to be effective against the infections caused by B. cenocepacia and other Gram-negative and-positive bacteria. C109 has a promising cellular target, the cell division protein FtsZ, and a recently developed PEGylated formulation make it an attractive molecule to counteract Burkholderia infections. However, the ability of efflux pumps to extrude it out of the cell represents a limitation...
Source: Frontiers in Microbiology - Category: Microbiology Source Type: research
In response to recurrent infection in cystic fibrosis (CF), powerful innate immune signals trigger polymorphonuclear neutrophil recruitment into the airway lumen. Exaggerated neutrophil proteolytic activity results in sustained inflammation and scarring of the airways. Consequently, neutrophils and their secretions are reliable clinical biomarkers of lung disease progression. As neutrophils are required to clear infection and yet a direct cause of airway damage, modulating adverse neutrophil activity while preserving their pathogen fighting function remains a key area of CF research. The factors that drive their pathologic...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Conditions:   Cystic Fibrosis;   Polymyxin B Intervention:   Other: Blood Draw Sponsors:   University of Michigan;   Cystic Fibrosis Foundation Recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
CONCLUSIONS: There is a lack of evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease. PMID: 32251534 [PubMed - as supplied by publisher]
Source: Cochrane Database of Systematic Reviews - Category: General Medicine Authors: Tags: Cochrane Database Syst Rev Source Type: research
CONCLUSIONS: We identified no trials for preventing silent cerebral infarcts in adults, or in children who do not have HbSS SCD. Long-term red blood cell transfusions may reduce the incidence of silent cerebral infarcts in children with abnormal TCD velocities, but may have little or no effect on children with normal TCD velocities. In children who are at higher risk of stroke and have not had previous long-term transfusions, long-term red blood cell transfusions probably reduce the risk of stroke, and other SCD-related complications (acute chest syndrome and painful crises). In children and adolescents at high risk of str...
Source: Cochrane Database of Systematic Reviews - Category: General Medicine Authors: Tags: Cochrane Database Syst Rev Source Type: research
Gender diverse youth with cystic fibrosis have unique health needs. Providers should be aware of existing health disparities in this population as well as aspects of gender-affirming care including hormone therapy, chest binding, and use of affirming language. This communication provides an introduction to these concerns.
Source: Journal of Cystic Fibrosis - Category: Respiratory Medicine Authors: Tags: Short Communication Source Type: research
In response to recent JCF Editorials regarding academic publishing, we highlight efforts to promote transparency, foster open access and recognize methodological contributions to CF clinical/translational research. We believe these efforts have been vital to improve methodological rigor and clinical impact of published research.
Source: Journal of Cystic Fibrosis - Category: Respiratory Medicine Authors: Tags: Letter to the Editor Source Type: research
The objective of this study was to design a PNA masking the binding site of the microRNA miR-145-5p present within the 3′UTR of the CFTR mRNA and to determine its activity in inhibiting miR-145-5p function, with particular focus on the expression of both CFTR mRNA and CFTR protein in Calu-3 cells. The results obtained support the concept that the PNA masking the miR-145-5p binding site of the CFTR mRNA is able to interfere with miR-145-5p biological functions, leading to both an increase of CFTR mRNA and CFTR protein content.
Source: Molecules - Category: Chemistry Authors: Tags: Brief Report Source Type: research
Authors: Kaur P, Kumar P, Randev S, Guglani V Abstract Allergic bronchopulmonary aspergillosis (ABPA) is an immunological disease complicating asthma or cystic fibrosis. An 8-year-old girl with no previous respiratory morbidity was diagnosed with ABPA on the basis of a raised eosinophil count and total and specific serum IgE levels combined with a positive skin-prick test for aspergillus and typical CT images of finger-in-glove hilar opacities and hyperattenuating mucous. She responded to treatment with itraconazole and corticosteroids and remains well. As far as we are aware, she is only the second child to be dia...
Source: Paediatrics and international child health - Category: Pediatrics Tags: Paediatr Int Child Health Source Type: research
Langawi et  al. [1] importantly highlight many ways in which the talents of women are being wasted, and the barriers that professional women encounter. Certainly parenthood is not the only one, but it is significant for many women. However, parenthood has ramifications not just for women; the role of men in c onception is well known, but the role of men in parenting has been neglected or worse. I am proud that one of my sons has just taken three months parental leave while his wife goes back to work, to look after their daughter.
Source: Journal of Cystic Fibrosis - Category: Respiratory Medicine Authors: Source Type: research
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