학술논문
Mechanisms by which the cystic fibrosis transmembrane conductance regulator may influence SARS-CoV-2 infection and COVID-19 disease severity.
Document Type
Academic Journal
Author
Tedbury PR; Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.; Department of Pediatrics, Children's Healthcare of Atlanta, Georgia, Atlanta, USA.; Manfredi C; Department of Pediatrics, Children's Healthcare of Atlanta, Georgia, Atlanta, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.; Degenhardt F; Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.; Conway J; Department of Pathology, Northeast Georgia Medical Center, Georgia, Gainesville, USA.; Horwath MC; Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA.; McCracken C; Department of Pediatrics, Children's Healthcare of Atlanta, Georgia, Atlanta, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.; Sorscher AJ; Department of Community and Family Medicine, Dartmouth University School of Medicine, New Hampshire, Hanover, USA.; Moreau S; Division of Laboratory Services, Elliot Hospital, New Hampshire, Manchester, USA.; Wright C; Division of Laboratory Services, Elliot Hospital, New Hampshire, Manchester, USA.; Edwards C; Department of Pathology, Northeast Georgia Medical Center, Georgia, Gainesville, USA.; Brewer J; Department of Pathology, Northeast Georgia Medical Center, Georgia, Gainesville, USA.; Guarner J; Department of Pathology and Laboratory Medicine, Emory Midtown Hospital, Georgia, Atlanta, USA.; de Wit E; Laboratory of Virology, Division of Intramural Research, NIAID, National Institutes of Health, Hamilton, Montana, USA.; Williamson BN; Laboratory of Virology, Division of Intramural Research, NIAID, National Institutes of Health, Hamilton, Montana, USA.; Suthar MS; Department of Pediatrics, Children's Healthcare of Atlanta, Georgia, Atlanta, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.; Ong YT; Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.; Department of Pediatrics, Children's Healthcare of Atlanta, Georgia, Atlanta, USA.; Roback JD; Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA.; Alter DN; Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, USA.; Holter JC; Department of Microbiology, Oslo University Hospital, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Karlsen TH; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.; Division of Surgery, Inflammatory Diseases and Transplantation, Research Institute for Internal Medicine, Oslo University Hospital Rikshospitalet and University of Oslo, Oslo, Norway.; Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Norwegian PSC Research Center, Oslo University Hospital Rikshospitalet, Oslo, Norway.; Section for Gastroenterology, Department of Transplantation Medicine, Division for Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.; Sacchi N; IBMDR, E.O. Ospedali Galliera, Genova, Italy.; Romero-Gómez M; Department of Digestive Diseases, Hospital Universitario Virgen del Rocío de Sevilla, Sevilla, Spain.; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.; Department of Liver, Digestive and Inflammatory Diseases, Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain.; Department of Medicine, University of Sevilla, Sevilla, Spain.; Digestive Diseases Unit, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville, University of Seville, Seville, Spain.; Invernizzi P; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy.; Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.; Fernández J; Hospital Clinic, University of Barcelona, and IDIBAPS, Barcelona, Spain.; European Foundation for the Study of Chronic Liver Failure (EF-CLIF), Barcelona, Spain.; Buti M; Liver Unit, Hospital Universitario Valle Hebron and CIBEREHD del Instituto Carlos III. Barcelona, Spain.; Albillos A; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.; Department of Gastroenterology, Hospital Universitario Ramón y Cajal, University of Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.; Julià A; Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Barcelona, Spain.; Valenti L; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.; Biological Resorce Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Milan, Italy.; Asselta R; Department of Biomedical Sciences, Humanitas University, Milan, Italy.; Department of Medical Genetics, IRCCS Humanitas Research Hospital, Milan, Italy.; Banales JM; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, San Sebastian, Spain.; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.; Bujanda L; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute - Donostia University Hospital, University of the Basque Country (UPV/EHU), CIBERehd, San Sebastian, Spain.; de Cid R; Genomes for Life-GCAT Lab, German Trias I Pujol Research Institute (IGTP), Badalona, Spain.; Franke A; Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.; Sarafianos SG; Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.; Department of Pediatrics, Children's Healthcare of Atlanta, Georgia, Atlanta, USA.; Hong JS; Department of Pediatrics, Children's Healthcare of Atlanta, Georgia, Atlanta, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.; Sorscher EJ; Department of Pediatrics, Children's Healthcare of Atlanta, Georgia, Atlanta, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.; Ehrhardt A; Department of Pediatrics, Children's Healthcare of Atlanta, Georgia, Atlanta, USA.; Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
Source
Publisher: Federation of American Societies for Experimental Biology Country of Publication: United States NLM ID: 8804484 Publication Model: Print Cited Medium: Internet ISSN: 1530-6860 (Electronic) Linking ISSN: 08926638 NLM ISO Abbreviation: FASEB J Subsets: MEDLINE
Subject
Language
English
Abstract
Patients with cystic fibrosis (CF) exhibit pronounced respiratory damage and were initially considered among those at highest risk for serious harm from SARS-CoV-2 infection. Numerous clinical studies have subsequently reported that individuals with CF in North America and Europe-while susceptible to severe COVID-19-are often spared from the highest levels of virus-associated mortality. To understand features that might influence COVID-19 among patients with cystic fibrosis, we studied relationships between SARS-CoV-2 and the gene responsible for CF (i.e., the cystic fibrosis transmembrane conductance regulator, CFTR). In contrast to previous reports, we found no association between CFTR carrier status (mutation heterozygosity) and more severe COVID-19 clinical outcomes. We did observe an unexpected trend toward higher mortality among control individuals compared with silent carriers of the common F508del CFTR variant-a finding that will require further study. We next performed experiments to test the influence of homozygous CFTR deficiency on viral propagation and showed that SARS-CoV-2 production in primary airway cells was not altered by the absence of functional CFTR using two independent protocols. On the contrary, experiments performed in vitro strongly indicated that virus proliferation depended on features of the mucosal fluid layer known to be disrupted by absent CFTR in patients with CF, including both low pH and increased viscosity. These results point to the acidic, viscous, and mucus-obstructed airways in patients with cystic fibrosis as unfavorable for the establishment of coronaviral infection. Our findings provide new and important information concerning relationships between the CF clinical phenotype and severity of COVID-19.
(© 2023 Federation of American Societies for Experimental Biology.)
(© 2023 Federation of American Societies for Experimental Biology.)