Cytomegalovirus in the Brain

Summary

Principal Investigator: Anthony N van den Pol
Affiliation: Yale University
Country: USA
Abstract: Within the brain, cytomegalovirus (CMV) is the leading viral cause of congenital disease, often producing serious neurological deficits. By attacking the developing CNS, CMV causes serious brain disorders that include microencephaly, epilepsy, deafness, microgyria, mental retardation, sensory loss, motor problems, and psychiatric disturbances. CMV is also 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 and within the brain, and the repercussions of this infection. A recombinant mouse CMV expressing GFP will be used to identify infected cells and track virus dispersal. CMV shows rapid dispersal in developing but not mature brain; the hypothesis that CMV can be spread through axonal transport, but only in the developing axon, will be tested. The hypothesis that interferons alpha/beta and gamma can reduce or eliminate CMV from the brain will be addressed with in vitro and in vivo experiments. Parallel experiments will test the hypothesis that CMV activates interferon pathways in the mature brain, but not in the developing brain. Mice lacking interferon receptors will be used to test further that CMV effects are mediated by these receptors and not by a non-specific action of CMV. An ultrastructural analysis will assess differential virus binding to immature and mature neurons, and determine where on the neuron surface CMV binds. In the immunocompromised CNS, the olfactory system shows the greatest levels of infection; we will address the hypothesis that the olfactory system is a weak link in the brain's protection against virus in SCID mice. The hypothesis that neurons that recover from CMV still show physiological dysfunction will be tested with whole cell patch clamp recording using current and voltage clamp and with fura-2 calcium digital imaging. CMV can remain latent for long periods. We will test the hypothesis that after interferon or gangciclovir treatment and recovery from infection, CMV can escape from neuronal latency, and establish a new round of productive infectious virus. These experiments will help us understand the mechanisms associated with CMV-induced neurological dysfunction, and how to combat the virus within the brain with minimal complications.
Funding Period: 2000-12-01 - 2011-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Direct and indirect inhibition by catecholamines of hypocretin/orexin neurons
    Ying Li
    Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    J Neurosci 25:173-83. 2005
  2. ncbi Targeting human glioblastoma cells: comparison of nine viruses with oncolytic potential
    Guido Wollmann
    Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, USA
    J Virol 79:6005-22. 2005
  3. ncbi CD4+ T-cell reconstitution reduces cytomegalovirus in the immunocompromised brain
    Jon D Reuter
    Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA
    J Virol 79:9527-39. 2005
  4. ncbi Cytomegalovirus induces interferon-stimulated gene expression and is attenuated by interferon in the developing brain
    Anthony N van den Pol
    Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, USA
    J Virol 81:332-48. 2007
  5. ncbi Variable deficiencies in the interferon response enhance susceptibility to vesicular stomatitis virus oncolytic actions in glioblastoma cells but not in normal human glial cells
    Guido Wollmann
    Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, USA
    J Virol 81:1479-91. 2007
  6. ncbi Bystander attenuation of neuronal and astrocyte intercellular communication by murine cytomegalovirus infection of glia
    Winson S C Ho
    Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, USA
    J Virol 81:7286-92. 2007
  7. ncbi Viral infection leading to brain dysfunction: more prevalent than appreciated?
    Anthony N van den Pol
    Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
    Neuron 64:17-20. 2009

Scientific Experts

Detail Information

Publications7

  1. ncbi Direct and indirect inhibition by catecholamines of hypocretin/orexin neurons
    Ying Li
    Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520, USA
    J Neurosci 25:173-83. 2005
    ..These data suggest that catecholamines evoke strong inhibitory actions on hypocretin neurons and suggest negative feedback from catecholamine cells that may be excited by hypocretin...
  2. ncbi Targeting human glioblastoma cells: comparison of nine viruses with oncolytic potential
    Guido Wollmann
    Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, USA
    J Virol 79:6005-22. 2005
    ..Together, these data suggest that four (VSV, Sindbis virus, MVMi, and MVMp) of the nine viruses studied merit further analysis for potential therapeutic actions on glioblastoma...
  3. ncbi CD4+ T-cell reconstitution reduces cytomegalovirus in the immunocompromised brain
    Jon D Reuter
    Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06510, USA
    J Virol 79:9527-39. 2005
    ..Systemic adoptive transfer may be a rapid and effective approach to preventing CMV entrance into the brain and for reducing neurotropic infection...
  4. ncbi Cytomegalovirus induces interferon-stimulated gene expression and is attenuated by interferon in the developing brain
    Anthony N van den Pol
    Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, USA
    J Virol 81:332-48. 2007
    ..These results suggest that coupling IFN administration with current treatments may reduce CMV infections in the developing brain...
  5. ncbi Variable deficiencies in the interferon response enhance susceptibility to vesicular stomatitis virus oncolytic actions in glioblastoma cells but not in normal human glial cells
    Guido Wollmann
    Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, USA
    J Virol 81:1479-91. 2007
    ..Together, our results demonstrate that activation of the interferon pathway protects normal human brain cells from VSV infection while maintaining the vulnerability of human glioblastoma cells to viral destruction...
  6. ncbi Bystander attenuation of neuronal and astrocyte intercellular communication by murine cytomegalovirus infection of glia
    Winson S C Ho
    Department of Neurosurgery, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, USA
    J Virol 81:7286-92. 2007
    ..These bystander effects would tend to cause further deterioration of cellular communication in the brain in addition to the problems caused by the loss of directly infected cells...
  7. ncbi Viral infection leading to brain dysfunction: more prevalent than appreciated?
    Anthony N van den Pol
    Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
    Neuron 64:17-20. 2009
    ..Virus infections of the brain can lead to transient or permanent neurologic or psychiatric dysfunction. Some of the complexities in establishing the causal role of viruses in brain disease are explored here...