Significance The brain parenchyma is considered to be “immune privileged” based upon differences between the innate and adaptive immune responses of the brain and those of the periphery. This work provides a clear demonstration of an innate immune response to direct infection by a virus, a response that is capable of limiting the spread of the virus along neuronal circuitry. The question of the brain parenchyma’s response to a viral infection has implications for the use of viruses as tools by neuroscientists, for vaccine development, and for potential clinical applications. Additionally, the approach used here provides a framework for further examination of the immunologic state of the brain as well as the mechanisms by which encephalitic viruses circumvent this response.