Functional Analysis of the Coronavirus Group-Specific Genes: Role in Virus-Host Interaction

Samenvatting

Coronaviruses contain -in addition to a characteristic set of essential genes- several so-called group-specific genes, that differ distinctly among the three coronavirus groups in their nature and genomic position, and that are specific for each group. Up till now, the coronavirus group-specific genes have hardly been studied. However, the observed attenuation of deletion mutant viruses in their natural hosts indicates that the functional significance of these genes relates to their role in virus-host interaction, possibly by modulating the host immune response. The aim of the proposed research is to elucidate the functions of these genes. The group-specific proteins of the murine hepatitis virus (MHV) and the SARS-coronavirus (SARS-CoV) will be studied in parallel. The following approach will be followed: 1) Establish which group-specific genes are expressed in infected cells. 2) Analyze the basic features (localization and biochemistry) of their expression products. 3) Identify interacting proteins by using two-hybrid screens. 4) Identify associated host cell pathways by microarray analysis of infected cells using recombinant viruses. The SARS-CoV research, as described in this proposal, will benefit from the headstart of the MHV research. The in depth analysis of the coronavirus group-specific genes is expected to open a new field of research. Examining the functional roles of the accessory proteins will help to understand how coronaviruses interact with their host, increase our knowledge of the host immune system and may suggest as yet unexploited avenues to combat coronavirus infections. This is desirable, since coronaviruses are not only pathogens with veterinary importance as well as a threat to mankind as shown by the (re)emergence of the SARS coronavirus.

Output

Proefschrift

  • M. Oostra(2007): SARS coronavirus membrane proteins  20 december 2007
  • M. Raaben(2009): Illuminating coronavirus-host interactions  3 september 2009

Wetenschappelijk artikel

  • P Whitley, M. Raaben, RA Setterquist, C.A.M. de Haan, D Bouwmeester, PJ Rottier(1998): Improved microarray expression profiling of virus-infected cells after removal of viral RNA BMC Genomics
  • FJ van Kuppeveld, MH Verheije, F. Reggiori, M Raaben, C.A.M. de Haan, M Mari, EG te Lintelo, PJ Rottier(1998): Mouse hepatitis coronavirus RNA replication depends on GBF1-mediated ARF1 activation Plos Pathogens
  • E.G. Lintelo, MC Hagemeijer, M van Gent, M Oostra, CP Bekker, PJ Rottier, C.A.M. de Haan(1998): Topology and membrane anchoring of the coronavirus replication complex: not all hydrophobic domains of nsp3 and nsp6 are membrane spanning Journal of Virology
  • C.A.M. de Haan, M. Raaben, T Wurdinger, E Te Lintelo, BJ Bosch, Z Li, PJ Rottier(2006): Cooperative involvement of the S1 and the S2 subunits of the murine coronavirus spike protein in receptor binding and extended host range Journal of Virology pp. 1352 - 1367
  • P.J.M. Rottier, M. Oostra, C.A.M. de Haan, R.J. de Groot(2006): Glycosylation of the severe acute respiratory syndrome coronavirus triple-spanning membrane proteins 3a and M Journal of Virology
  • C.A.M. de Haan, PJ Rottier(2006): Hosting the severe acute respiratory syndrome coronavirus: specific cell factors required for infection Cell. Microbiol. pp. 1211 - 1218
  • M.H. Verheije, C.A.M. de Haan, M. Oostra, E.G. te Lintelo, M. Deijs, P.J.M. Rottier(2007): Localization and membrane topology of coronavirus nonstructural protein 4: involvement of the early secretory pathway in replication Journal of Virology pp. 12323 - 12336
  • M. Oostra, P.J.M. Rottier, C.A.M. de Haan(2007): The 29-nucleotide deletion present in human but not animal severe acute respiratory syndrome coronaviruses disrupts the functional expression of open reading frame 8 Journal of Virology pp. 13876 - 13888
  • P.J.M. Rottier, M. Raaben, C.A.M. de Haan, M.J. Groot Koerkamp(2007): Mouse hepatitis coronavirus replication induces host translational shutoff and mRNA decay, with concomitant formation of stress granules and processing bodies Cellular Microbiology
  • C.A.M. de Haan, F. Reggiori(2008): Are Nidoviruses hijacking the autophagy machinery? Autophagy
  • PJ Rottier, HJ Prins, M Raaben, AC Martens, C.A.M. de Haan(2009): Non-invasive imaging of mouse hepattis coronavirus infection reveals determinants of viral replication and spread in vivo Cell Microbiol
  • MJ Groot Koerkamp, C.A.M. de Haan, PJM Rottier, M Raaben(2009): Type I interferon receptor-independent and -dependent host transcriptional responses to mouse hepatitis coronavirus infection in vivo. BMC genomics
  • CAM de Haan, CC Posthuma, M Raaben, M Kikkert, EJ Snijder, PJM Rottier, MH Verheije, JW Drijfhout, EG te Lintelo(2010): The ubiquitin-proteasome system plays an important role during various stages of the coronavirus infection cycle. Journal of Virology
  • PJM Rottier, CAM de Haan, M Raaben, GC Grinwis(2010): The proteasome inhibitor Velcade enhances rather than reduces disease in mouse hepatitis coronavirus-infected mice. Journal of Virology

Kenmerken

Projectnummer

700.54.421

Hoofdaanvrager

Dr. C.A.M. de Haan

Verbonden aan

Universiteit Utrecht, Faculteit Diergeneeskunde, Virologie

Uitvoerders

Dr. C.A.M. de Haan, Dr. M. Raaben

Looptijd

01/11/2004 tot 19/01/2010