Mechanism of BBB permeability enhancement in rabies virus infection
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Infection with laboratory-attenuated rabies virus (RABV) enhances Blood-brain Barrier (BBB) permeability, which has been demonstrated to be an important factor for host survival, since it allows immune effectors to enter the central nervous system (CNS) and clear RABV. To probe the mechanism by which RABV infection enhances BBB permeability, the expressions of tight junction (TJ) proteins in the CNS were investigated following intracranial inoculation with laboratory-attenuated or wild-type (wt) RABV. BBB permeability was significantly enhanced in mice infected with laboratory-attenuated, but not wt, RABV. The expression levels of TJ proteins were decreased in mice infected with laboratory-attenuated, but not wt, RABV, suggesting that enhancement of BBB permeability is associated with the reduction of TJ protein expression in RABV infection. Brain extracts prepared from mice infected with laboratory-attenuated, but not wt, RABV reduced TJ protein expression in BMECs. It was found that brain extracts from mice infected with laboratory-attenuated RABV contained significantly higher levels of inflammatory chemokines/cytokines than those from mice infected with wt RABV. Pathway analysis indicates that type II interferon (IFN-γ) is located in the center of the cytokine network in the RABV-infected mouse brain, and neutralization of IFN-γ reduced both the disruption of BBB permeability in vivo and the down-regulation of TJ protein expression in vitro. These findings indicate that the enhancement of BBB permeability and the reduction of TJ protein expression are not due to RABV infection per se but due to virus-induced inflammatory chemokines/cytokines. Among these chemokines/cytokines, IFN-γ expression was detected in the late stage of RABV infection. However, chemokine CXCL10 was found to be the most highly and earliest expressed after infection with laboratory-attenuated RABV, it is hypothesized that CXCL10 could be the initiation factor for reduction in TJ protein expression and enhancement of BBB permeability. Therefore the temporal and spatial expression of CXCL10 was determined in the mouse brain after infection with RABV. Expression of CXCL10 was initially detected in neurons as early as day 3 post infection before it was detected in microglia (day 6 pi) and astrocytes (day 9 pi) in RABV-infected mice. Neutralization of CXCL10 reduced IFN-γ production, Th17 cell infiltration, loss of TJ protein expression, and the enhancement of BBB permeability in mice infected with laboratory-attenuated RABV. Thus neuronal CXCL10 induced by RABV initiates cascades leading to expression of other inflammatory chemokines/cytokines and enhancement of the BBB permeability.