Japanese Encephalitis Virus Disrupts Cell-Cell Junctions and Affects the Epithelial Permeability Barrier Functions

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.

Zika-Virus-Encoded NS2A Disrupts Mammalian Cortical Neurogenesis by Degrading Adherens Junction Proteins

“…Additional deficits in radial glial fiber scaffolding may explain the positional defects of newborn neurons. Notably, two other flaviviruses, West Nile Virus and Japanese Encephalitis Virus, also interact with AJ proteins and target junction proteins for lysosomal degradation in non-neuronal cells via viral proteins different from NS2A (Agrawal et al, 2013; Medigeshi et al, 2009). It will be useful in the future to engineer ZIKVs with NS2A mutations that have high infection capacity but with no impact on neural stem cells to test how our identified mechanism contributes to the overall pathological impact of ZIKV on cortical neurogenesis.…”

Influenza virus damages the alveolar barrier by disrupting epithelial cell tight junctions

“…In vitro, the transduction of cells with claudin-4 increased the TER by ∼50% [40]. Moreover, several different viruses are known to disrupt claudin expression and increase permeability across monolayers of several different cell types [6][7][8]. It is therefore tempting to speculate that IAV-induced loss of claudin-4 played a major role in the observed decline of the TER.…”

“…By forming at the sites of cell-cell contact, the AJC regulates paracellular permeability and ensures barrier integrity. Several viruses are known to damage the AJC of a wide variety of different cell types [5][6][7][8][9]. However, to the best of our knowledge no study to date has investigated whether IAV can damage the AJC of alveolar epithelial cells.…”

Junctional proteins of the blood-brain barrier: New insights into function and dysfunction

“…Increased kinetics of lysosomes and autophagosomes and localization of junctional proteins (i.e., claudin-2, Cx43, Ve-cadherin) to intracellular compartments where they are targeted for lysosomal degradation was found in the regulation of epithelial and endothelial barriers exposed to Japanese encephalitis virus (JEV), nutrient starvation or macrophage migration inhibitory factor (MIF). [148][149][150] Similar processes may apply to the BBB, but direct proof is still lacking.…”