ABSTRACT The inner ear is perfused by vessels that provide oxygen and nutrients to support the activity of hearing. This separation between the blood and inner ear fluids is maintained by tightly connected cells that reinforce the blood vessels and ensure that small molecules, proteins, and cells remain inside the blood vessel. The structural elements that form this barrier are called the blood-labyrinth barrier. This barrier plays an important role in regulating the entry of white blood cells from the blood stream into the inner ear. When the immune system is activated, this barrier becomes leaky, and white blood cells leave the vessel lumen, enter the inner compartment, and can then eliminate germs or unwanted cells. These white blood cells are also capable of damaging normal tissues that are not intended targets of the inflammatory response. The first part of this study examines the developing blood-labyrinth barrier in animals that are born with a viral infection called cytomegalovirus (CMV). CMV is an important cause of hearing loss in the newborn population and we do not fully understand how it causes hearing loss. We have limited options to address hearing loss in infants born with CMV. This infection occurs at a time when the blood labyrinth and blood brain barriers are not yet mature. Infection that begins in utero cause long term deficits that may be related to abnormal development of these vascular barriers. The second aim will identify which cells are directly targeted by the virus and whether cell killing by viral infection contributes to loss of hearing function. The third group of experiments will explore the role of the interferons in contributing to hearing loss in mice. We will explore the effects of reducing IFN signaling specifically in blood vessels after viral infection to disrupt the events that could lead to hearing loss while maintaining the important antiviral effects of IFNs. The goal is to improve our understanding of how the immune system works in the inner ear, what elements of the immune system are critical for preventing or eliminating infections, and which of its functions might contribute to damage and hearing loss. Immunosuppressive and anti-inflammatory agents have been used in cases of sensorineural hearing loss with success, but their side effects limit their effectiveness. Thus, there is an opportunity to study the contributions of inflammation and immunity to design better medications and improve treatment of progressive hearing loss.