The importance of virus neutralizating antibodies and blood-brain barrier permeability enhancement in clearing rabies virus from the central nervous system
MetadataShow full item record
Rabies has been known as a highly fatal zoonotic disease for centuries. It is widely accepted that there is no effective treatment, and rabies is almost always fatal once neurological symptoms develop. Although the loss of blood-brain barrier (BBB) integrity and infiltration of inflammatory cells have often been associated with pathological changes in the central nervous system (CNS) when infected by viruses, transiently increased BBB permeability during attenuated rabies virus (RABV) infection has been found to be helpful in clearing the virus from the CNS and preventing neurological sequelae. Furthermore, the clearance of attenuated RABV from the CNS was correlated with infiltration of B cells into the CNS, expressing high levels of κ-light chain mRNA. The main goal of this study is to provide a better understanding of factors influencing the pathogenicity of rabies viruses to develop a foundation for developing a possible therapy for clinical rabies. Our results demonstrated that virus neutralizating antibodies (VNAs) were not produced, and the BBB remained intact throughout wild-type RABV infections as previous studies reported. Based on these two major findings during wild-type rabies infections, we developed a way to clear an established rabies infection from the CNS in a mouse model. This includes passive administration of VNAs and intracerebral injection of monocyte chemotactic protein 1 (MCP-1), a chemokine known to transiently enhance BBB permeability. The treatment was given to mice 5 days after infection with wild-type RABV. The results demonstrated that, even in the absence of B cells, administration of VNA in the periphery could lead to RABV clearance from the CNS and prevent the development of rabies once the BBB permeability is enhanced. In conclusion, VNA was found to be capable of clearing RABV from the CNS in both immunocompetent and immunocompromised mice, as long as the BBB permeability is enhanced.