Congenital human cytomegalovirus (HCMV) infection represents an important cause of neurological damage in children and is the leading cause of non-familial hearing loss in the US. Little is understood about the pathogenesis of this infection because suitable models of central nervous system (CNS) infection are lacking. We have developed a murine model of congenital HCMV infection which recapitulates many of the histopathological and neurodevelopmental abnormalities described in congenital HCMV infections, including hearing loss in surviving mice. In contrast to earlier models, newborn mice injected peripherally with murine CMV develop viremia and subsequently, encephalitis. Because newborn mice are neurodevelopmentally and immunologically equivalent to late 2nd trimester human fetuses, this model has also enabled us to study resolution of this virus infection in a developing animal. In this proposal we will study aspects of the CNS infection in these animals including mechanisms of neuroinvasion, the contribution of innate immune responses in clearance of the virus from the CNS, and the interplay between innate immunity and adaptive immune responses in clearance of virus from the CNS. Lastly, the contribution of both innate and adaptive immunity in persistent CNS infection in adult mice infected as newborns will be studied. We anticipate that parameters of the pathogenesis of CMV infection in the developing CNS will be identified from these studies. Furthermore, we believe that these findings can be translated directly into more focused studies in humans that could lead to new approaches for prevention and treatment of this important infection.

Public Health Relevance

Human cytomegalovirus infection in the developing fetus is a major cause of brain disease in infants and children. Currently no vaccines or treatment exist for this infection that is transmitted from the mother to the fetus. This project will utilize a highly related mouse virus and a mouse model of this disease to understand the characteristics of this infection that result in brain infection and the immune responses that limit virus growth and damage to the developing brain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Virology - B Study Section (VIRB)
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Wong, May
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University of Alabama Birmingham
Schools of Medicine
United States
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Seleme, Maria C; Kosmac, Kate; Jonjic, Stipan et al. (2017) Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice. J Virol 91:
Li, Xiao-Jun; Liu, Xi-Juan; Yang, Bo et al. (2015) Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells. J Virol 89:6792-804
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Bradford, Russell D; Yoo, Young-Gun; Golemac, Mijo et al. (2015) Murine CMV-induced hearing loss is associated with inner ear inflammation and loss of spiral ganglia neurons. PLoS Pathog 11:e1004774
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Pan, Xing; Li, Xiao-Jun; Liu, Xi-Juan et al. (2013) Later passages of neural progenitor cells from neonatal brain are more permissive for human cytomegalovirus infection. J Virol 87:10968-79
Knight, Andrea; Arnouk, Hilal; Britt, William et al. (2013) CMV-independent lysis of glioblastoma by ex vivo expanded/activated V?1+ ?? T cells. PLoS One 8:e68729
Kosmac, Kate; Bantug, Glenn R; Pugel, Ester P et al. (2013) Glucocorticoid treatment of MCMV infected newborn mice attenuates CNS inflammation and limits deficits in cerebellar development. PLoS Pathog 9:e1003200
Yamamoto, Aparecida Y; Mussi-Pinhata, Marisa Marcia; Isaac, Myriam de Lima et al. (2011) Congenital cytomegalovirus infection as a cause of sensorineural hearing loss in a highly immune population. Pediatr Infect Dis J 30:1043-6
Slavuljica, Irena; Busche, Andreas; Babic, Marina et al. (2010) Recombinant mouse cytomegalovirus expressing a ligand for the NKG2D receptor is attenuated and has improved vaccine properties. J Clin Invest 120:4532-45

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