Cytomegalovirus is the leading viral cause of congenital disease, often producing serious neurological deficits. CMV attacks the developing central nervous system (CNS) resulting in serious brain disorders that include microencephaly, epilepsy, deafness, microgyria, mental retardation, sensory loss, motor problems, and psychiatric disturbances. In addition, CMV is a clinically important opportunistic virus that can lead to serious neurological disease in AIDS patients. Despite the clinical importance of CMV infections of the brain, relatively little experimental work has been done in this area, and many basic questions remained unanswered. The present application addresses basic mechanisms of viral spread into the brain, and once in the brain, spread by intracellular transport or extracellular diffusion to other brain cells. The hypothesis that CMV can be spread through axonal transport will be studied with in vitro and in vivo models. Although CMV appears to have no absolute host cell preference in the brain, the hypothesis that CMV shows relative cellular preferences will be tested in living brain slices at different developmental ages. A recombinant mouse CMV expressing green fluorescent protein will be used to identify infected cells. Neurons in vitro are all killed by CMV, whereas mature neurons in vivo are protected against CMV. Using a mouse model of immunosuppression, parallel to AIDS, we will test the hypothesis that cell-mediated immunity protects neurons in vivo from CMV proliferation. Neuronal activity plays an important role in establishing the correct circuitry during brain development. The hypothesis that early infection by CMV can generate disturbances in the electrophysiological activity of developing neurons will be tested with whole cell patch clamp recording using current and voltage clamp electrophysiology, and with calcium digital imaging, using primary mouse neuron cultures and brain slices. Virus mediated changes in intracellular ion levels, ion currents, transmitter responses, and membrane properties will be compared in CMV infected and control cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI048854-01A1
Application #
6399705
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Beisel, Christopher E
Project Start
2001-07-01
Project End
2006-05-31
Budget Start
2001-07-01
Budget End
2002-05-31
Support Year
1
Fiscal Year
2001
Total Cost
$349,481
Indirect Cost
Name
Yale University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Wollmann, Guido; Ozduman, Koray; van den Pol, Anthony N (2012) Oncolytic virus therapy for glioblastoma multiforme: concepts and candidates. Cancer J 18:69-81
van den Pol, Anthony N (2009) Viral infection leading to brain dysfunction: more prevalent than appreciated? Neuron 64:17-20
van den Pol, Anthony N; Ozduman, Koray; Wollmann, Guido et al. (2009) Viral strategies for studying the brain, including a replication-restricted self-amplifying delta-G vesicular stomatis virus that rapidly expresses transgenes in brain and can generate a multicolor golgi-like expression. J Comp Neurol 516:456-81
Wollmann, Guido; Robek, Michael D; van den Pol, Anthony N (2007) Variable deficiencies in the interferon response enhance susceptibility to vesicular stomatitis virus oncolytic actions in glioblastoma cells but not in normal human glial cells. J Virol 81:1479-91
Ho, Winson S C; van den Pol, Anthony N (2007) Bystander attenuation of neuronal and astrocyte intercellular communication by murine cytomegalovirus infection of glia. J Virol 81:7286-92
van den Pol, Anthony N; Robek, Michael D; Ghosh, Prabhat K et al. (2007) Cytomegalovirus induces interferon-stimulated gene expression and is attenuated by interferon in the developing brain. J Virol 81:332-48
Wollmann, Guido; Tattersall, Peter; van den Pol, Anthony N (2005) Targeting human glioblastoma cells: comparison of nine viruses with oncolytic potential. J Virol 79:6005-22
Reuter, Jon D; Wilson, Jean H; Idoko, Kimberly E et al. (2005) CD4+ T-cell reconstitution reduces cytomegalovirus in the immunocompromised brain. J Virol 79:9527-39
Li, Ying; van den Pol, Anthony N (2005) Direct and indirect inhibition by catecholamines of hypocretin/orexin neurons. J Neurosci 25:173-83
Reuter, Jon D; Gomez, Daniel L; Wilson, Jean H et al. (2004) Systemic immune deficiency necessary for cytomegalovirus invasion of the mature brain. J Virol 78:1473-87

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