Abstract
Japanese encephalitis virus (JEV) is a neurotropic flavivirus, which causes viral encephalitis leading to death in about 20–30% of severely-infected people. Although JEV is known to be a neurotropic virus its replication in non-neuronal cells in peripheral tissues is likely to play a key role in viral dissemination and pathogenesis. We have investigated the effect of JEV infection on cellular junctions in a number of non-neuronal cells. We show that JEV affects the permeability barrier functions in polarized epithelial cells at later stages of infection. The levels of some of the tight and adherens junction proteins were reduced in epithelial and endothelial cells and also in hepatocytes. Despite the induction of antiviral response, barrier disruption was not mediated by secreted factors from the infected cells. Localization of tight junction protein claudin-1 was severely perturbed in JEV-infected cells and claudin-1 partially colocalized with JEV in intracellular compartments and targeted for lysosomal degradation. Expression of JEV-capsid alone significantly affected the permeability barrier functions in these cells. Our results suggest that JEV infection modulates cellular junctions in non-neuronal cells and compromises the permeability barrier of epithelial and endothelial cells which may play a role in viral dissemination in peripheral tissues.
Highlights
Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus from the family Flaviviridae
As in the case of epithelial cells, we found that JEV-infected primary endothelial cells had lower levels of tight junction proteins claudin-5 and occludin and adherens junction (AJ) proteins a and b-catenin whereas zona occludens (ZO)-1 levels were only marginally reduced (Figure 1C)
We propose that the effect of JEV infection on junctional proteins leads to disruption of cellular junctions resulting in perturbation of paracellular barrier functions of polarized cells
Summary
Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus from the family Flaviviridae. In various mouse models of JEV, the virus has been isolated from kidney, liver and spleen indicating that JEV infects peripheral tissues in vivo [5,6]. Previous studies have reported abnormalities in liver and kidney function and gastric hemorrhage in pediatric and adult patients infected with JEV [7,8]. It is not known if these are direct effects of JEV replication in these tissues or due to host response. Virus replication in epithelial and endothelial cells of peripheral tissues that form the permeability barrier may play a key role in the overall outcome of JEV infection in vivo. TJ acts as functional diffusion barrier for pathogens and many viruses either use components of TJs for establishing infection in epithelial or endothelial cells or modulate the TJ components to gain access to the tissue space and for further spread of the infection [13,14]
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