Rabies virus clearance from the central nervous system

Abstract

Rabies, a neurological disease associated with replication in central nervous system (CNS) tissues of any of a number of rabies viruses endemic in nature, is generally fatal. Prophylactic medical intervention is immune mediated and directed at preventing the spread of the virus from a peripheral site of exposure to the CNS. While individuals rarely develop immune responses capable of clearing the virus from CNS tissues, a variety of laboratory-attenuated rabies viruses are readily cleared from the CNS tissues in animal models. By comparing immune responses to wild-type and attenuated rabies viruses in these models, we have discovered that the latter induce processes required for immune effector infiltration into CNS tissues that are absent from lethal infections. Predominant among these are activities of cells of the neurovascular unit (NVU) that promote an interaction with circulating immune cells. In the absence of this interaction, the specialized barrier function of the NVU remains intact and circulating virus-specific immune effectors are largely excluded from infected CNS tissues. Studies of mixed infections with wild-type and attenuated rabies viruses reveal that wild-type rabies viruses fail to trigger, rather than inhibit, the interactions between immune cells and the NVU required for virus clearance from the CNS. These studies provide insights into how immune effectors with the capacity to clear the virus may be delivered into CNS tissues to contain a wild-type rabies virus infection. However, to apply immunotherapeutic strategies beyond the initial stages of CNS infection, further insights into the fate of the infected cells during virus clearance are needed.