West nile virus capsid degradation of claudin proteins disrupts epithelial barrier function.
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.
Medigeshi
Guruprasad R
GR
Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon 97006, USA.
Hirsch
Alec J
AJ
Brien
James D
JD
Uhrlaub
Jennifer L
JL
Mason
Peter W
PW
Wiley
Clayton
C
Nikolich-Zugich
Janko
J
Nelson
Jay A
JA
D000818:Animals; D018938:Caco-2 Cells; D002213:Capsid / Q000378:metabolism*; D002463:Cell Membrane Permeability; D002522:Chlorocebus aethiops; D062445:Claudin-1; D062465:Claudin-3; D057167:Claudins; D004847:Epithelial Cells / Q000821:virology; D006801:Humans; D007684:Kidney Tubules / Q000821:virology*; D008353:Mannitol / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D019108:Tight Junctions / Q000821:virology; D014709:Vero Cells; D014901:West Nile Fever / Q000821:virology*; D014902:West Nile virus / Q000472:pathogenicity*
C568108:CLDN1 protein, human; C568122:CLDN3 protein, human; D062445:Claudin-1; D062465:Claudin-3; D057167:Claudins; C568113:Cldn1 protein, mouse; C113371:Cldn2 protein, mouse; C568123:Cldn3 protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D008353:Mannitol