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Borna Disease Virus as a tool to study viral interference with neuronal integrity

Abstract:

Borna disease virus (BDV) is an enveloped RNA virus with a genome of negative polarity which replicates in the nucleus of the infected cell. It encodes for only six proteins, the nucleoprotein (N), the X protein, the phosphoprotein (P), the matrix protein (M), the glycoprotein (G) and the polymerase (L). Intriguingly, BDV can persistently infect neurons of the central nervous system without causing general cell death, reflecting a favorable adaptation to the brain. However, this adaptation of BDV is accompanied by subtle consequences for infected neurons, including changes in the neuronal and synaptic plasticity. Most strikingly, BDV infection causes the specific loss of dentate granule cells in the hippocampus of infected rats. Therefore, BDV represents a unique model to gain insights into specific neuronal degeneration processes in the brain. Using hippocampus slice cultures (left panel) and dissociated neuronal cultures (right panel) we are currently studying various aspects of neuronal plasticity and survival after BDV-infection. Furthermore, we want to unveil the viral strategies required to establish a persistent infection in neuronal tissue.

This project is carried out in close cooperation with the lab of Prof. Heimrich (Institute of Anatomy and Cell Biology, University of Freiburg) and funded by the DFG and a fellowship to Chia-Chin Lin by the Spemann Graduate School Freiburg.

Infection of hippocampus slice cultures with Borna Disease Virus (BDV) Left panel: A hippocampus slice cultures obtained from a newborn Lewis rat was infected with BDV and stained 2 weeks post infection for BDV (Green), calbindin (Red) and cell nucleus (DAPI), which is a maker for dentate granule cells. mf, mossy fiber, dgc, dentate granule cells. Right panel: Dissociated primary neuronal cultures were obtained from the cortex of newborn Lewis rats. They were infected with BDV for 1 week and subjected to immunofluorescence analysis by using specific antibodies against BDV (blue) and Map2 (red), a specific marker of neurons. Bar 40 μm.

Investigators:

Chia-Ching Lin
Arnold Martin
Masayuki Horie

In collaboration with:

• Norbert Hübner (MDC Berlin)
• Daniel Gonzalez-Dunia (Inserm, University of Toulouse)
• Philipp Dautel and Milton T. Stubbs (Institute for Biochemistry and Biotechnology, Martin-Luther-University, Halle)
• Keizo Tomonaga, (Department of Virology,Research Institute for Microbial Diseases, Osaka University, Japan)

Selected References:

• Gonzalez-Dunia, D., R. Volmer, D. Mayer, and M. Schwemmle.
  Borna disease virus interference with neuronal plasticity
  Virus Res 111: 224-34 (2005)
  >PubMed
• Mayer, D., S. Baginsky, and M. Schwemmle.
  Isolation of viral ribonucleoprotein complexes from infected cells by tandem affinity purification
  Proteomics 5: 483-7 (2005)
  >PubMed
• Mayer, D., H. Fischer, U. Schneider, B. Heimrich, and M. Schwemmle.
  Borna disease virus replication in organotypic hippocampal slice cultures from rats results in selective damage of dentate granule cells
  J Virol 79: 11716-23 (2005)
  >PubMed
• Chase, G., D. Mayer, A. Hildebrand, R. Frank, Y. Hayashi, K. Tomonaga, and M. Schwemmle.
  Borna disease virus matrix protein is an integral component of the viral ribonucleoprotein complex that does not interfere with polymerase activity
  J Virol 81: 743-9 (2007)
  >PubMed
• Heimrich, B., D. A. Hesse, Y. J. Wu, S. Schmid, and M. Schwemmle.
  Borna disease virus infection alters synaptic input of neurons in rat dentate gyrus
  Cell Tissue Res 338: 179-90 (2009)
  >PubMed
• Prat, C. M., S. Schmid, F. Farrugia, N. Cenac, G. Le Masson, M. Schwemmle, and D. Gonzalez-Dunia.
  Mutation of the protein kinase C site in borna disease virus phosphoprotein abrogates viral interference with neuronal signaling and restores normal synaptic activity
  PLoS Pathog 5: e1000425 (2009)
  >PubMed
• Schmid, S., P. Metz, C. M. Prat, D. Gonzalez-Dunia, and M. Schwemmle
  Protein kinase C-dependent phosphorylation of Borna disease virus P protein is required for efficient viral spread
  Arch Virol 155: 789-93 (2010)
  >PubMed
• Schwemmle M, Heimrich B.
  Viral interference with neuronal integrity: what can we learn from the Borna disease virus?
  Cell Tissue Res 344: 13-6 (2011)
  >PubMed