The blood-brain barrier (BBB) is a specialization of the neurovasculature that regulates contact between the contents of the circulation and CNS tissues. The integrity of the BBB must be transiently compromised for immune effectors to enter the CNS tissues to clear a neurotropic virus infection. During the clearance of a laboratory attenuated rabies virus strain, CVS-F3, from the CNS, increased BBB permeability is CD4 T cell dependent and associated with the production of IFN-? and nitrotyrosine formation in corresponding areas of the neurovasculature. We have recently established that infection with wildlife rabies viruses (RV), such as the highly pathogenic silver-haired bat-associated rabies virus (SHBRV), is lethal despite the induction of innate and adaptive immunity because the maintenance of BBB integrity prevents immune effectors from reaching the CNS tissues. This is the first description of a process that allows a neurotropic virus to escape immune clearance by interfering with the mechanism responsible for enhanced BBB permeability. Understanding how this occurs is important with respect to the design of therapeutic strategies for the emerging SHBRV infection of humans as well as, likely, for other neurotropic infections. The objective of this project is to identify the precise steps in the anti-viral, immune-mediated induction of enhanced BBB permeability that occurs in CVS-F3 infected animals but are absent in SHBRV-infected animals. Immunohistochemical, cellular and molecular techniques will be used to characterize the activity of CD4 T cells, vascular endothelial cells, and BBB-associated astrocytes as well as the changes that occur at the BBB during infection. ? ? ? ?
