Mechanisms of apoptosis in the central nervous system

Summary

Principal Investigator: Kenneth Tyler
Abstract: Viral-induced encephalitis remains a major cause of morbidity and mortality throughout the world. Effective therapies are available for only a few neurotropic viruses, and even when these infections are optimally treated, residual mortality and neurological sequelae remain considerable. No established treatment exists for flaviviruses, including West Nile virus, (WNV) the most common cause of epidemic encephalitis in the United States and Japanese encephalitis virus (JEV), the most common cause of viral encephalitis worldwide. Similarly, although treatment with acyclovir improves the outcome of herpes simplex type-1 (HSV-1) encephalitis, the most common acute sporadic encephalitis in the Western world, residual morbidity and mortality remain significant. Further, nearly half of all emerging viral diseases are associated with encephalitis or serious neurological clinical symptoms. Novel strategies for identifying and treating viral central nervous system (CNS) infections are thus urgently needed. OBJECTIVE 1. To identify specific cellular genes that are differentially regulated during virus-induced encephalitis and have potential as novel therapeutic targets for these diseases. Available data suggests that encephalitis induced by a variety of viruses is associated with the activation of similar cellular signaling pathways. We have previously performed microarray analysis to determine genes that are differentially regulated during reovirus-induced encephalitis. We now propose to perform microarray analysis of mRNA extracted from the brains of mice during HSV-1- and WNV-induced encephalitis and to identify alterations in cellular gene expression and cellular signaling pathways that are common all 3 viruses. These genes are expected to have a high likelihood of providing therapeutic targets for encephalitis induced by a variety of viruses. The applicability of using altered expression of these genes or activation of these pathways as therapeutic targets for virus-induced encephalitis will be further assessed by determining the expression of these genes and activation of these pathways in the brain following infection with other encephalitic viruses, including JEV, Sindbis virus (SINV), and Venezualen equine encephalitis virus (VEEV). OBJECTIVE 2. Evaluation of novel therapeutic targets for virus-induced encephalitis. The experiments proposed in specific aim 1 will identify cellular genes and signaling pathways that have potential as therapeutic targets for virus-induced encephalitis. We propose to evaluate these potential therapeutic targets by determining virus-induced pathogenesis using treatments designed to block expression of these genes and pathways. PUBLIC HEALTH RELEVANCE: Viral-induced encephalitis remains a major cause of morbidity and mortality throughout the world. The proposed studies will identify cellular genes and signaling pathways that are activated during virus-induced encephalitis. In addition, the proposed studies will evaluate the role of these genes and pathways as novel therapeutic targets for these diseases.
Funding Period: 2005-01-01 - 2010-08-31
more information: NIH RePORT

Top Publications

  1. pmc Type I interferon signaling limits reoviral tropism within the brain and prevents lethal systemic infection
    Kalen R Dionne
    Medical Scientist Training Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
    J Neurovirol 17:314-26. 2011
  2. pmc Impact of rituximab-associated B-cell defects on West Nile virus meningoencephalitis in solid organ transplant recipients
    Marilyn E Levi
    Division of Infectious Diseases, Department of Internal Medicine, University of Colorado Denver, Anschutz Medical Campus, Denver, CO 80045, USA
    Clin Transplant 24:223-8. 2010
  3. pmc Emerging viral infections of the central nervous system: part 1
    Kenneth L Tyler
    Neurology B 182, Research Complex 2, University of Colorado Denver Health Sciences Center, 12700 E 19th Ave, Aurora, CO 80045, USA
    Arch Neurol 66:939-48. 2009
  4. pmc Emerging viral infections of the central nervous system: part 2
    Kenneth L Tyler
    Department of Neurology, University of Colorado Denver Health Sciences Center, Aurora, CO 80045, USA
    Arch Neurol 66:1065-74. 2009
  5. pmc Disrupted glutamate transporter expression in the spinal cord with acute flaccid paralysis caused by West Nile virus infection
    Pennelope K Blakely
    Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI 48109 2200, USA
    J Neuropathol Exp Neurol 68:1061-72. 2009
  6. pmc Gene expression in the brain during reovirus encephalitis
    Kenneth L Tyler
    Department of Neurology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA
    J Neurovirol 16:56-71. 2010
  7. pmc Caspase-3 activation is required for reovirus-induced encephalitis in vivo
    J David Beckham
    Department of Medicine, Division of Infectious Diseases, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado 80045, USA
    J Neurovirol 16:306-17. 2010
  8. pmc Critical role for death-receptor mediated apoptotic signaling in viral myocarditis
    Roberta L Debiasi
    Department of Pediatrics, Children s National Medical Center and George Washington University School of Medicine, Washington, DC 20010, USA
    J Card Fail 16:901-10. 2010
  9. pmc A brain slice culture model of viral encephalitis reveals an innate CNS cytokine response profile and the therapeutic potential of caspase inhibition
    Kalen R Dionne
    Medical Scientist Training Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA
    Exp Neurol 228:222-31. 2011
  10. pmc The proapoptotic Bcl-2 protein Bax plays an important role in the pathogenesis of reovirus encephalitis
    Heather M Berens
    Department of Microbiology, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO 80045, USA
    J Virol 85:3858-71. 2011

Scientific Experts

  • Penny Clarke
  • Kenneth L Tyler
  • Roberta L Debiasi
  • Marilyn E Levi
  • J David Beckham
  • Larry E Davis
  • Shelley D Miyamoto
  • Robin J Goody
  • Kalen R Dionne
  • Cristen C Hoyt
  • Sarah M Richardson-Burns
  • Heather M Berens
  • Stephanie A Schittone
  • Pennelope K Blakely
  • Angela K Zimmermann
  • Daniel A Linseman
  • Ron J Bouchard
  • F Alexandra Loucks
  • Shoshona S Le
  • Kristi A Lorenzen
  • John M Galvin
  • J Smith Leser
  • Bette K Kleinschmidt-DeMasters
  • David N Irani
  • Kira Rubtsova
  • Emily K Schroeder
  • Reid A Phelps
  • Sarah Richardson-Burns
  • Eric R Kandel
  • Kim A Heidenreich
  • Klaus Aktories
  • Hiroshi Udo
  • Bridget A Robinson
  • Holger Barth

Detail Information

Publications30

  1. pmc Type I interferon signaling limits reoviral tropism within the brain and prevents lethal systemic infection
    Kalen R Dionne
    Medical Scientist Training Program, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
    J Neurovirol 17:314-26. 2011
    ..T3 reovirus tropism was extended in IFNAR(-/-) brains to include dentate neurons, ependymal cells, and meningeal cells indicating that reovirus tropism within the CNS is dependent upon type I interferon signaling...
  2. pmc Impact of rituximab-associated B-cell defects on West Nile virus meningoencephalitis in solid organ transplant recipients
    Marilyn E Levi
    Division of Infectious Diseases, Department of Internal Medicine, University of Colorado Denver, Anschutz Medical Campus, Denver, CO 80045, USA
    Clin Transplant 24:223-8. 2010
    ..She experienced a rapidly progressive and devastating neurological course despite treatment and died three wk after onset of her symptoms. Autopsy revealed extensive meningoencephalomyelitis...
  3. pmc Emerging viral infections of the central nervous system: part 1
    Kenneth L Tyler
    Neurology B 182, Research Complex 2, University of Colorado Denver Health Sciences Center, 12700 E 19th Ave, Aurora, CO 80045, USA
    Arch Neurol 66:939-48. 2009
    ....
  4. pmc Emerging viral infections of the central nervous system: part 2
    Kenneth L Tyler
    Department of Neurology, University of Colorado Denver Health Sciences Center, Aurora, CO 80045, USA
    Arch Neurol 66:1065-74. 2009
    ....
  5. pmc Disrupted glutamate transporter expression in the spinal cord with acute flaccid paralysis caused by West Nile virus infection
    Pennelope K Blakely
    Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI 48109 2200, USA
    J Neuropathol Exp Neurol 68:1061-72. 2009
    ..The pathogenesis of this increasingly common disorder likely involves immune response and excitotoxicity mechanisms that are potential therapeutic targets...
  6. pmc Gene expression in the brain during reovirus encephalitis
    Kenneth L Tyler
    Department of Neurology, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, USA
    J Neurovirol 16:56-71. 2010
    ....
  7. pmc Caspase-3 activation is required for reovirus-induced encephalitis in vivo
    J David Beckham
    Department of Medicine, Division of Infectious Diseases, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado 80045, USA
    J Neurovirol 16:306-17. 2010
    ..Examination of brains of long-term survivors of reovirus infection among caspase-3 (-/-) mice showed that these mice eventually clear their CNS viral infection, and do not manifest residual or delayed CNS tissue injury...
  8. pmc Critical role for death-receptor mediated apoptotic signaling in viral myocarditis
    Roberta L Debiasi
    Department of Pediatrics, Children s National Medical Center and George Washington University School of Medicine, Washington, DC 20010, USA
    J Card Fail 16:901-10. 2010
    ..The apoptotic signaling pathways that are activated during viral myocarditis and the role that these pathways play in disease pathogenesis have not been clearly delineated...
  9. pmc A brain slice culture model of viral encephalitis reveals an innate CNS cytokine response profile and the therapeutic potential of caspase inhibition
    Kalen R Dionne
    Medical Scientist Training Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045, USA
    Exp Neurol 228:222-31. 2011
    ..Cultured brain slices not only serve to model events occurring during viral encephalitis, but can also be utilized to investigate aspects of pathogenesis and therapy that are not experimentally accessible in vivo...
  10. pmc The proapoptotic Bcl-2 protein Bax plays an important role in the pathogenesis of reovirus encephalitis
    Heather M Berens
    Department of Microbiology, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, CO 80045, USA
    J Virol 85:3858-71. 2011
    ....
  11. pmc Cardiac cell-specific apoptotic and cytokine responses to reovirus infection: determinants of myocarditic phenotype
    Shelley D Miyamoto
    Department of Pediatrics, University of Colorado Denver Health Sciences Center, Denver, Colorado, USA
    J Card Fail 15:529-39. 2009
    ..The pathophysiologic mechanisms underlying viral myocarditis are not well defined. As a result, effective treatments do not exist and viral myocarditis remains a potentially lethal infection of the heart...
  12. pmc Fas-mediated apoptotic signaling in the mouse brain following reovirus infection
    Penny Clarke
    Departments of Neurology, University of Colorado Denver Health Sciences Programs, Anschutz Medical Campus, Aurora, Colorado 80045, USA
    J Virol 83:6161-70. 2009
    ....
  13. pmc Reovirus activates transforming growth factor beta and bone morphogenetic protein signaling pathways in the central nervous system that contribute to neuronal survival following infection
    J David Beckham
    Department of Medicine, University of Colorado Denver, Aurora, CO 80045, USA
    J Virol 83:5035-45. 2009
    ....
  14. pmc Apoptosis in animal models of virus-induced disease
    Penny Clarke
    Department of Neurology, University of Colorado, Denver Health Sciences Programs, Anschutz Medical Campus, Aurora, Colorado 80045, USA
    Nat Rev Microbiol 7:144-55. 2009
    ....
  15. pmc North American encephalitic arboviruses
    Larry E Davis
    New Mexico Veterans Affairs Health Care System, 1500 San Pedro Drive SE, Albuquerque, NM 87108, USA
    Neurol Clin 26:727-57, ix. 2008
    ..Unfortunately, no antiviral drugs are approved for the treatment of arbovirus infection and current therapy is supportive...
  16. ncbi Minocycline delays disease onset and mortality in reovirus encephalitis
    Sarah M Richardson-Burns
    Neuroscience Program, University of Colorado Health Sciences Center, Denver, CO 80262, USA
    Exp Neurol 192:331-9. 2005
    ....
  17. pmc Mechanisms of apoptosis during reovirus infection
    P Clarke
    Department of Neurology B 182, University of Colorado Health Sciences Center, 4200 East 9th Ave, Denver, CO 80262, USA
    Curr Top Microbiol Immunol 289:1-24. 2005
    ..This review examines the mechanisms of reovirus-induced apoptosis and investigates the possibility that inhibition of apoptosis may provide a novel strategy for limiting virus-induced tissue damage following infection...
  18. pmc Mechanisms of reovirus-induced cell death and tissue injury: role of apoptosis and virus-induced perturbation of host-cell signaling and transcription factor activation
    P Clarke
    Department of Neurology, University of Colorado Health Sciences Center, 4200 East 9th Ave, Denver, CO 80262, USA
    Viral Immunol 18:89-115. 2005
    ..The potential of reovirus-induced oncolysis in therapy of human cancers is currently being investigated in phase I/II clinical trials...
  19. pmc Inhibition of NF-kappa B activity and cFLIP expression contribute to viral-induced apoptosis
    P Clarke
    Department of Neurology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA
    Apoptosis 10:513-24. 2005
    ..These results demonstrate that inhibition of stimulus-induced activation of NF-kappaB and the resulting decrease in cFLIP expression promote reovirus-induced apoptosis...
  20. pmc Reovirus infection of the CNS enhances iNOS expression in areas of virus-induced injury
    Robin J Goody
    Department of Neurology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA
    Exp Neurol 195:379-90. 2005
    ..Our findings provide the first evidence of reovirus-induced iNOS expression and the first demonstration that NO inhibits mammalian reovirus replication, suggesting that NO may play an antiviral role during reovirus infection...
  21. pmc Inhibition of Rac GTPase triggers a c-Jun- and Bim-dependent mitochondrial apoptotic cascade in cerebellar granule neurons
    Shoshona S Le
    Research Service, Veterans Affairs Medical Center, Denver, Colorado 80220, USA
    J Neurochem 94:1025-39. 2005
    ..These results indicate that Rac acts downstream of integrins and growth factors to promote neuronal survival by repressing c-Jun/Bim-mediated mitochondrial apoptosis...
  22. pmc West Nile virus meningoencephalitis
    Roberta L Debiasi
    Department of Pediatrics, University of Colorado Health Sciences Center, Denver, CO 80262, USA
    Nat Clin Pract Neurol 2:264-75. 2006
    ..In this review, we discuss epidemiology, risk factors, clinical features, diagnosis and prognosis of WNV meningoencephalitis, along with potential treatments...
  23. pmc Down-regulation of cFLIP following reovirus infection sensitizes human ovarian cancer cells to TRAIL-induced apoptosis
    Penny Clarke
    Department of Neurology, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box B182, Denver, Colorado 80262, USA
    Apoptosis 12:211-23. 2007
    ..The combination of reovirus and TRAIL thus represents a promising new therapeutic approach for the treatment of ovarian cancer...
  24. pmc Novel strategy for treatment of viral central nervous system infection by using a cell-permeating inhibitor of c-Jun N-terminal kinase
    J David Beckham
    Department of Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA
    J Virol 81:6984-92. 2007
    ..Given the efficacy of the inhibitor in protecting mice from viral encephalitis, JNK inhibition represents a promising and novel treatment strategy for viral encephalitis...
  25. pmc Glutathione binding to the Bcl-2 homology-3 domain groove: a molecular basis for Bcl-2 antioxidant function at mitochondria
    Angela K Zimmermann
    Eleanor Roosevelt Institute, Department of Biological Sciences, University of Denver, Denver, Colorado 80208, USA
    J Biol Chem 282:29296-304. 2007
    ..We conclude that this novel GSH binding property of Bcl-2 likely plays a central role in its antioxidant function at mitochondria...
  26. pmc JAK-STAT signaling pathways are activated in the brain following reovirus infection
    Robin J Goody
    Departments of Neurology, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA
    J Neurovirol 13:373-83. 2007
    ..The results demonstrate activation of a type I IFN-mediated, JAK-dependent STAT signaling pathway following reovirus infection and suggest that STAT1 is a key component of host defense mechanisms against reovirus infection in the brain...
  27. pmc Infectious disease - developments in the field of Creutzfeldt-Jakob disease
    J David Beckham
    University of Colorado Health Sciences Center, Denver, CO, USA
    Rev Neurol Dis 4:168-72. 2007
  28. pmc Experimental reovirus-induced acute flaccid paralysis and spinal motor neuron cell death
    Robin J Goody
    Department of Neurology, University of Colorado Health Sciences Center, Denver, CO 80262, USA
    J Neuropathol Exp Neurol 67:231-9. 2008
    ..This study represents the first detailed characterization of a novel and highly efficient experimental model of virus-induced AFP that will facilitate evaluation of therapeutic strategies targeting virus-induced paralysis...
  29. pmc Nonstructural protein sigma1s is a determinant of reovirus virulence and influences the kinetics and severity of apoptosis induction in the heart and central nervous system
    Cristen C Hoyt
    Department of Neurology B 182, University of Colorado Health Sciences Center, 4200 E 9th Ave, Denver, CO 80262, USA
    J Virol 79:2743-53. 2005
    ..These results demonstrate that sigma1s is a determinant of the magnitude and extent of reovirus-induced apoptosis in both the heart and CNS and thereby contributes to reovirus pathogenesis and virulence...