Human cytomegalovirus (HCMV) is a widespread human pathogen that infects 50-95% of the adult population worldwide. In healthy individuals, primary HCMV infection is cleared from all tissues except the submandibular salivary gland (SMG), where it can persist for several months. After this period of persistence, HCMV eventually becomes latent for the life of the host. Reactivation of latent HCMV is rare in individuals with healthy immune systems, but is far more common in individuals with compromised immune systems. These include people with congenital or acquired immune deficiencies, organ transplant recipients, or any patients taking immunosuppressive drugs. In immune compromised individuals, primary HCMV infection or reactivation of latent infection can cause serious and even fatal health complications. Even when it is not fatal, reactivation of HCMV in the salivary gland can cause several oral pathologies that greatly limit quality of life, such as increased dental cavities, periodontal infections, and chronic dry mouth. HCMV can also be passed from mother to fetus during pregnancy, and the resulting neonatal HCMV infection can result in severe birth defects. Due to the strict species tropism of the CMV family members, HCMV cannot be studied in an animal model. However, murine cytomegalovirus (MCMV) is very similar to HCMV in terms of genetics, structure, and mechanisms of infection. Thus, MCMV is an appropriate animal model to study HCMV infection. Like HCMV, MCMV persists in the SMG of the host before becoming latent. Also like in humans, murine natural killer (NK) cells are crucial for the early containment of MCMV. NK cells are innate immune cells that respond to MCMV infection by directly killing infected cells, and by releasing pro-inflammatory cytokines such as IFN-? that stimulate further immune responses. Recently, the Brossay laboratory has discovered that the NK cells of the SMG are hyporesponsive to MCMV infection: they are activated upon infection, but their IFN-? response is diminished compared to NK cells of the spleen, liver, and blood. The SMG is a delicate tissue, vulnerable to irreversible damage by either unchecked viral replication or an extensive inflammatory immune response. My hypothesis is that the diminished effector response of the SMG NK cells allows MCMV to persist in this organ at levels too low to cause direct damage, while at the same time preserving the SMG tissues from extensive inflammatory damage. In Aim 1, I will determine whether SMG NK cells control MCMV replication to low levels. In Aim 2, I will determine whether SMG NK cells can be induced to respond to MCMV infection, or whether their hyporesponsive phenotype is intrinsic and irreversible. The research described in this proposal will elucidate the factors allowing MCMV to persist in the SMG of the mammalian host. This knowledge could eventually lead to the development of more effective therapies against this ubiquitous human pathogen.