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      Effects of Pseudomonas aeruginosa on CFTR chloride secretion and the host immune response

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          Abstract

          In the healthy lung the opportunistic pathogen, Pseudomonas aeruginosa, is rapidly eliminated by mucociliary clearance, a process that is dependent on the activity of the CFTR anion channel that, in concert with a number of other transport proteins, regulates the volume and composition of the periciliary surface liquid. This fluid layer is essential to enable cilia to clear pathogens from the lungs. However, in cystic fibrosis (CF), mutations in the CFTR gene reduce Cl and H C O 3 secretion, thereby decreasing periciliary surface liquid volume and mucociliary clearance of bacteria. In CF this leads to persistent infection with the opportunistic pathogen, P. aeruginosa, which is the cause of reduced lung function and death in ~95% of CF patients. Others and we have conducted studies to elucidate the effects of P. aeruginosa on wild-type and Phe508del-CFTR Cl secretion as well as on the host immune response. These studies have demonstrated that Cif (CFTR inhibitory factor), a virulence factor secreted by P. aeruginosa, is associated with reduced lung function in CF and induces the ubiquitination and degradation of wt-CFTR as well as TAP1, which plays a key role in viral and bacterial antigen presentation. Cif also enhances the degradation of Phe508del-CFTR that has been rescued by ORKAMBI, a drug approved for CF patients homozygous for the Phe508del-CFTR mutation, thereby reducing drug efficacy. This review is based on the Hans Ussing Distinguished Lecture at the 2016 Experimental Biology Meeting given by the author.

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          Author and article information

          Journal
          Am J Physiol Cell Physiol
          Am. J. Physiol., Cell Physiol
          ajpcell
          ajpcell
          AJPCELL
          American Journal of Physiology - Cell Physiology
          American Physiological Society (Bethesda, MD )
          0363-6143
          1522-1563
          1 April 2017
          25 January 2017
          1 April 2018
          : 312
          : 4
          : C357-C366
          Affiliations
          Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth , Hanover, New Hampshire
          Author notes
          Address for reprint requests and other correspondence: B. A. Stanton, Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755 (e-mail: Bruce.A.Stanton@ 123456Dartmouth.edu ).
          Article
          PMC5407021 PMC5407021 5407021 C-00373-2016 C-00373-2016
          10.1152/ajpcell.00373.2016
          5407021
          28122735
          f1171be8-87da-43b8-9530-6c3a4df7c6ee
          Copyright © 2017 the American Physiological Society
          History
          : 3 January 2017
          : 20 January 2017
          : 21 January 2017
          Funding
          Funded by: NIH
          Award ID: R01 HL074175
          Award ID: P30 GM106394
          Funded by: http://doi.org/10.13039/100000897 Cystic Fibrosis Foundation (CFF)
          Award ID: STANTO19R0
          Award ID: STANTO16GO
          Categories
          Review
          Hans Henriksen Ussing Distinguished Lectureship of the Epithelial Transport Group, 2016

          ORKAMBI,cystic fibrosis,CFTR,outer membrane vesicles, Pseudomonas aeruginosa

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