CXCL10 and blood-brain barrier modulation in rabies virus infection

Rabies is a lethal neurological disease caused by the neurotropic rabies virus (RABV). It can be prevented by prompt vaccination along with hyper-immune serum containing virus neutralizing antibodies (VNA) after a recognized exposure. However, there is no effective treatment available once the clinical symptoms appears. Various studies have shown that the laboratory-attenuated, but not the wild-type (wt), RABV can be cleared from the central nervous system (CNS), not solely due to its ability to induce innate and adaptive immunities such as production of chemokines, cytokines and VNA, and activation of immune cells, but also due to its ability to enhance the blood-brain barrier (BBB) permeability. BBB consists of a complex network of cellular system consisting of endothelial cells (ECs) which are tightly bound together by tight junction (TJ) proteins (claudins, occludin and zonula occludens-1), pericytes and astrocytes end feet, allowing selective transport of molecules to enter the CNS. Infiltration of immune effector cells from the periphery to the site of infection depends upon a cascade of events including the production of chemokines and cytokines, and modulation of BBB permeability, initiated by CNS resident cells. Thus, any abatement in the initiation and production of immune response may lead to a failure to induce BBB permeability changes and a protective immune response. Attenuated RABVs are known to induce the expression of proinflammatory chemokines and cytokines, especially those related to interferon signaling pathways, whereas wt RABVs stimulate little or no inflammatory responses [1]. Roy et al., 2007 have shown that the failure to open the BBB leads to the lethal outcome after infection with silverhaired bat RABV in mice [2]. Thus, for the effective clearance of RABV from the CNS, the presence of VNA and the enhancement of BBB permeability are required [3]. However, the mechanism by which RABV infection initiates BBB permeability enhancement was unclear. In these issues of the Journal of virology, Chai et al., investigated the mechanism by which attenuated RABV infection initiates BBB permeability enhancement in mice [4, 5]. Initially, it was observed that the attenuated RABV infection in mice enhances BBB permeability by reducing the TJ proteins and inducing infiltration of inflammatory cells into the CNS. However, either attenuated or wt RABV infection did not reduce TJ proteins on brain microvascular endothelial cells (BMEC) in vitro, indicating that RABV infection per se is not involved in BBB modulation. It was further found that the extracts from the brains of mice infected with attenuated RABV alone, could significantly reduce the TJ proteins. Analysis of mice brain extracts showed the presence of high levels of chemokine and cytokines. Ingenuity pathway analysis of immune networks indicates that IFN-γ is the center molecule which is directly linked with CXCL10, CXCLl9, CCL5, IL-17, IL-12, IL-6 and VEGF. Likewise, the induction of innate immunity, particularly interferon mediated expression of chemokines and cytokines, and their association with BBB permeability enhancement have been reported previously [1]. Most importantly, it has been shown that the BBB permeability can be ameliorated Editorial