Cytomegalovirus (CMV) is the leading cause of human congenital viral infection and the major source of nonhereditary congenital deafness. A significant new development in the clinical perspective of congenital CMV infection is the impact of acquired immune deficiency syndrome (AIDS): more than 90 percent of AIDS patients are co-infected with CMV, and congenital CMV infection rates in HIV-infected mothers are elevated by up to 2100 percent. The host and viral factors regulating congenital CMV infections in AIDS mothers are unknown. Pediatric AIDS (PAIDS) has been recognized as a significant new etiologic consideration for ototlaryngologists and audiologists. The pediatric population with AIDS is more susceptible to central nervous system (CNS) pathology than adults: 96 percent of children dead from AIDS exhibited CNS abnormalities at autopsy. While auditory and vestibular disease is common in PADS, the mechanisms responsible for these sensory system pathologies are poorly understood. However, opportunistic coinfection of the auditory system by CMV is thought to be an important source of PADS-related hearing loss. During the past grant period we successfully developed new SCID (severe combined immunodeficiency) mutant mice animal models of congenital and perinatal murine CMV (MCMV) infections in the developing auditory system. Our studies with these new SCID mouse models confirmed, for the first time, congenital MCMV infection of the inner ear and auditory CNS. Notably, as with human opportunistic CMV infections in immunodeficient individuals, both congenital and perinatal MCMV infections in SCID mice caused progressive postnatal viral replication and auditory system neuropathologies. We propose to utilize our new SCID/MCMV models to investigate the following basic questions: 1) How does congenital and perinatal MCMV infection pathologically influence neuronal migration and apoptosis in the developing inner ear and auditory CNS? 2) What molecular mechanisms regulate bidirectional communication between the immune and neuroendocrine systems during the development of congenital and pennatal MCMV auditory system infections? 3) Can ganciclovir antiviral treatment prevent congenital auditory system MCMV infections? 4) Is persistent congenital MCMV infection reactivated in the inner ear and brain when ganciclovir treatment is terminated? An interdisciplinary approach will be used to investigate the clinical symptoms, immunologic, virologic, histopathologic, molecular biologic and electrophysiologic aspects of congenital MCMV infections within the peripheral and central auditory system of immunodeficient SCID mice.
| Reuss, Stefan; Banica, Ovidiu; Elgurt, Mirra et al. (2016) Neuroglobin Expression in the Mammalian Auditory System. Mol Neurobiol 53:1461-1477 |
