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 AIDS: more than 90% of AIDS patients are co-infected with CMV, and the rate of congenital CMV infection is elevated up to 2100% in HIV-infected mothers. The host and viral factors regulating congenital CMV auditory infections in immunodeficient mothers are unknown. The development of animal congenital CMV infection models has been hindered by the species-specific nature of the virus. Previously, we established a guinea pig CMV (GPCMV) model of human congenital CMV auditory system neuropathologies. However, the GPCMV congenital infection model has numerous experimental disadvantages. We have no overcome these efficiencies by developing, for the first time, a murine CMV (MCMV) model of natural transplacental congenital infection using severe combined immunodeficient (SCID) mice. This new model exhibits congenital MCMV infection of the peripheral and central auditory system, and offers the advantages of the extensive background information, immunological reagents, an molecular probes available for mice. We now propose to utilize SCID mice, and transgenic lines of mice developed by our collaborators, to investigate the following basic questions about AIDS-associated congenital CMV infection: 1) How is the pathogenesis of congenital MCMV labyrinthritis and auditory central nervous system infection different in immunodeficient SCID mice? 2) Does congenital MCMV infection in SCID mice pathologically alter the patterns of cerebral cytokine expression in the developing auditory system? 3) What role does tissue-specific expression of the retinoic acid receptor superfamily play in enhancing the etiopathogenesis of congenital MCMV infection in SCID mouse inner ear and brain? 4) To what extent does cellular expression of CMV major immediate-early promoter (MIEP) limit cellular susceptibility to congenital MCMV infection in the developing SCID mouse auditory system. An interdisciplinary approach will be used to investigate the clinical symptoms, immunologic, virologic, pathologic and molecular biologic aspects of congenita auditory system MCMV infections in SCID mice.
|Reuss, Stefan; Banica, Ovidiu; Elgurt, Mirra et al. (2016) Neuroglobin Expression in the Mammalian Auditory System. Mol Neurobiol 53:1461-1477|