This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stonebraker, J. R.
Right arrow Articles by Pickles, R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stonebraker, J. R.
Right arrow Articles by Pickles, R. J.

 Previous Article  |  Next Article 

Journal of Virology, December 2004, p. 13755-13768, Vol. 78, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.24.13755-13768.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Glycocalyx Restricts Adenoviral Vector Access to Apical Receptors Expressed on Respiratory Epithelium In Vitro and In Vivo: Role for Tethered Mucins as Barriers to Lumenal Infection

Jaclyn R. Stonebraker,1 Danielle Wagner,1 Robert W. Lefensty,1 Kimberlie Burns,1 Sandra J. Gendler,2 Jeffrey M. Bergelson,3 Richard C. Boucher,1 Wanda K. O'Neal,1 and Raymond J. Pickles1,4*

Cystic Fibrosis/Pulmonary Research and Treatment Center,1 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina,4 Mayo Clinic Scottsdale, Scottsdale, Arizona,2 Division of Immunologic and Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania3

Received 16 March 2004/ Accepted 30 July 2004

Inefficient adenoviral vector (AdV)-mediated gene transfer to the ciliated respiratory epithelium has hindered gene transfer strategies for the treatment of cystic fibrosis lung disease. In part, the inefficiency is due to an absence of the coxsackie B and adenovirus type 2 and 5 receptor (CAR) from the apical membranes of polarized epithelia. In this study, using an in vitro model of human ciliated airway epithelium, we show that providing a glycosylphosphatidylinositol (GPI)-linked AdV receptor (GPI-CAR) at the apical surface did not significantly improve AdV gene transfer efficiency because the lumenal surface glycocalyx limited the access of AdV to apical GPI-CAR. The highly glycosylated tethered mucins were considered to be significant glycocalyx components that restricted AdV access because proteolytic digestion and inhibitors of O-linked glycosylation enhanced AdV gene transfer. To determine whether these in vitro observations are relevant to the in vivo situation, we generated transgenic mice expressing GPI-CAR at the surface of the airway epithelium, crossbred these mice with mice that were genetically devoid of tethered mucin type 1 (Muc1), and tested the efficiency of gene transfer to murine airways expressing apical GPI-human CAR (GPI-hCAR) in the presence and absence of Muc1. We determined that AdV gene transfer to the murine airway epithelium was inefficient even in GPI-hCAR transgenic mice but that the gene transfer efficiency improved in the absence of Muc1. However, the inability to achieve a high gene transfer efficiency, even in mice with a deletion of Muc1, suggested that other glycocalyx components, possibly other tethered mucin types, also provide a significant barrier to AdV interacting with the airway lumenal surface.

* Corresponding author. Mailing address: CF/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, 7021 Thurston Bowles, Chapel Hill, NC 27759-7248. Phone: (919) 966-1522. Fax: (919) 966-5178. E-mail: branston{at}med.unc.edu.

Journal of Virology, December 2004, p. 13755-13768, Vol. 78, No. 24
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.24.13755-13768.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Diaz, F., Gravotta, D., Deora, A., Schreiner, R., Schoggins, J., Falck-Pedersen, E., Rodriguez-Boulan, E. (2009). Clathrin adaptor AP1B controls adenovirus infectivity of epithelial cells. Proc. Natl. Acad. Sci. USA 106: 11143-11148 [Abstract] [Full Text]  
  • Russell, W. C. (2009). Adenoviruses: update on structure and function. J. Gen. Virol. 90: 1-20 [Abstract] [Full Text]  
  • Kolodkin-Gal, D., Zamir, G., Edden, Y., Pikarsky, E., Pikarsky, A., Haim, H., Haviv, Y. S., Panet, A. (2008). Herpes Simplex Virus Type 1 Preferentially Targets Human Colon Carcinoma: Role of Extracellular Matrix. J. Virol. 82: 999-1010 [Abstract] [Full Text]  
  • Blalock, T. D., Spurr-Michaud, S. J., Tisdale, A. S., Heimer, S. R., Gilmore, M. S., Ramesh, V., Gipson, I. K. (2007). Functions of MUC16 in Corneal Epithelial Cells. IOVS 48: 4509-4518 [Abstract] [Full Text]  
  • Newby, C. M., Sabin, L., Pekosz, A. (2007). The RNA Binding Domain of Influenza A Virus NS1 Protein Affects Secretion of Tumor Necrosis Factor Alpha, Interleukin-6, and Interferon in Primary Murine Tracheal Epithelial Cells. J. Virol. 81: 9469-9480 [Abstract] [Full Text]  
  • Young, H. W. J., Williams, O. W., Chandra, D., Bellinghausen, L. K., Perez, G., Suarez, A., Tuvim, M. J., Roy, M. G., Alexander, S. N., Moghaddam, S. J., Adachi, R., Blackburn, M. R., Dickey, B. F., Evans, C. M. (2007). Central Role of Muc5ac Expression in Mucous Metaplasia and Its Regulation by Conserved 5' Elements. Am. J. Respir. Cell Mol. Bio. 37: 273-290 [Abstract] [Full Text]  
  • Rowe, R. K., Pekosz, A. (2006). Bidirectional Virus Secretion and Nonciliated Cell Tropism following Andes Virus Infection of Primary Airway Epithelial Cell Cultures. J. Virol. 80: 1087-1097 [Abstract] [Full Text]  
  • Sims, A. C., Baric, R. S., Yount, B., Burkett, S. E., Collins, P. L., Pickles, R. J. (2005). Severe Acute Respiratory Syndrome Coronavirus Infection of Human Ciliated Airway Epithelia: Role of Ciliated Cells in Viral Spread in the Conducting Airways of the Lungs. J. Virol. 79: 15511-15524 [Abstract] [Full Text]  
  • Zhang, Y., Bergelson, J. M. (2005). Adenovirus Receptors. J. Virol. 79: 12125-12131 [Full Text]  
  • Zhang, L., Bukreyev, A., Thompson, C. I., Watson, B., Peeples, M. E., Collins, P. L., Pickles, R. J. (2005). Infection of Ciliated Cells by Human Parainfluenza Virus Type 3 in an In Vitro Model of Human Airway Epithelium. J. Virol. 79: 1113-1124 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»