The principle research area of the Hooper laboratory is CNS immunity and, particularly, the balance between protective and destructive neuroinflammatory processes. CNS tissues are protected from immune mechanisms by the blood-brain barrier (BBB) and a major focus of the lab is on mechanisms that modulate BBB integrity and how these impact protective versus pathological CNS inflammatory and neurodegenerative conditions. Important questions are how does the therapeutic delivery of immune effectors across the BBB during virus clearance differ from pathological immune cell invasion into the CNS parenchyma and how are these processes regulated? We were the first to show that peroxynitrite-dependent radicals open the BBB during a CNS inflammatory response and that the sources of these radicals differ between pathological and therapeutic immune cell invasion into CNS tissues. Our current projects are directed at understanding the mechanisms through which therapeutic immune cells and molecules, such as lymphocytes and antibodies, are naturally delivered to CNS tissues during a CNS immune response such that these processes may be manipulated therapeutically for the treatment of neurotropic virus infection, neurodegenerative disease, and brain cancer. For example, we have discovered that the protective alterations in BBB function required for immune effector infiltration into CNS tissues during the therapeutic clearance of attenuated rabies viruses are inhibited during infection with highly pathogenic rabies viruses. This enables pathogenic rabies viruses to evade immune clearance and cause a lethal infection despite eliciting strong anti-viral immune responses in the periphery. We are assessing various strategies to circumvent this block and deliver therapeutic reagents into the infected CNS tissues, approaches that will also be used to target immune effectors to CNS tumors. From the opposite perspective we are continuing our long-term studies of peroxynitrite-dependent radical inactivation as a means to maintain BBB integrity and prevent potentially pathological cells and factors from infiltrating into CNS tissues. We pioneered the approach of raising serum levels of urate, a natural peroxynitrite-dependent radical scavenger, for the treatment of CNS autoimmunity, a strategy that is the foundation of several clinical trials in multiple sclerosis (MS) and Parkinsons disease. Current studies are directed at understanding the pathways through which the peroxynitrite-dependent radicals inactivated by urate mediate their effects on the BBB and CNS tissues.