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Journal of Virology, June 2009, p. 6125-6134, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.02617-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

West Nile Virus Capsid Degradation of Claudin Proteins Disrupts Epithelial Barrier Function{triangledown}

Guruprasad R. Medigeshi,1,{dagger} Alec J. Hirsch,1,{dagger}* James D. Brien,1,{ddagger} Jennifer L. Uhrlaub,2 Peter W. Mason,3 Clayton Wiley,4 Janko Nikolich-Zugich,2 and Jay A. Nelson1*

Vaccine and Gene Therapy Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, Oregon 97006,1 Department of Immunobiology, University of Arizona, Medical Research Building, 1656 E. Mabel Street, Tucson, Arizona 85724,2 3.206B Mary Moody Northen Pavilion, Department of Pathology and Sealy Center for Vaccine Development, University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-0436,3 Department of Pathology, University of Pittsburgh Medical Center, Presbyterian Hospital A506, 200 Lothrop Street, Pittsburgh, Pennsylvania 152134

Received 18 December 2008/ Accepted 3 April 2009

During acute infection, West Nile virus (WNV) has been reported to infect a variety of cell types in various tissues of both experimentally and naturally infected hosts. Virus infects epithelial cells in the skin, kidney, intestine, and testes, although the importance of these findings is unclear. In the current study, we have observed that WNV infection of kidney tubules in mice coincides with the loss of expression of several members of the claudin family. Proteins of this family are often involved in epithelial barrier formation and function. WNV infection of epithelial cells in culture resulted in a decrease in the transepithelial electrical resistance, an increase in the efflux of mannitol across the monolayer, and a loss of intracellular levels of claudin-1 to -4. WNV capsid alone was sufficient for the degradation event, which was mediated through lysosomal proteases. Since epithelial cells are frequent sites of WNV infection, these observations imply a potential mechanism for virus dissemination and extraneural pathogenesis.

* Corresponding author. Mailing address: Vaccine and Gene Therapy Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006. Phone for Jay A. Nelson: (503) 418-2710. Phone for Alec J. Hirsch: (503) 418-2784. Fax: (503) 418-2701. E-mail for Jay A. Nelson: nelsonj{at}ohsu.edu. E-mail for Alec J. Hirsch: hirschal{at}ohsu.edu

{triangledown} Published ahead of print on 15 April 2009.

{dagger} These authors contributed equally to this study.

{ddagger} Present address: Division of Infectious Diseases, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110-1093.

Journal of Virology, June 2009, p. 6125-6134, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.02617-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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