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Christiane Wobus

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Primary Appointment: Microbiology and Immunology
Primary PIBS Dept.: Microbiology and Immunology
PubMed Name: wobus ce
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 DESCRIPTION OF RESEARCH
 
The Wobus lab is interested in mechanisms of norovirus - host interactions in vitro and in vivo.
Human noroviruses are the major cause of nonbacterial epidemic gastroenteritis worldwide resulting in substantial morbidity and economic loss. They cause an estimated 23 million cases of gastroenteritis per year in the USA alone and are frequent visitors to cruise ships, hospitals, daycare centers and other places were crowds gather. However, despite the importance for public health, human norovirus research has been severely hampered by the lack of a small animal model and in vitro replication system. Therefore, little or no information is available in many areas of norovirus biology and no directed disease prevention and control strategies exist for these viruses.
With our recent discovery of the first murine norovirus (MNV-1) and hence the availability of a small animal model, the development of the first in vitro culture system and reverse genetics system for a norovirus, we have a unique system to begin a detailed analysis of different aspects of norovirus biology. We are particularly interested in early events in the viral life cycle. We previously demonstrated that murine norovirus (MNV) 1 infects murine macrophages (Mf) and dendritic cells (DC) but not other murine cells or cells of non-murine origin. More importantly, this inability to infect certain cells can be overcome by transfection of noroviral RNA into non-permissive cells, leading to the production of infectious virus particles. These data demonstrate that the initial steps of receptor binding and/or entry are crucial in determining which cells are supportive of norovirus infection. In addition, these early events are major factors in determining species and tissue specificity, virulence and ultimately the outcome of a virus infection.
Therefore, our main focus is currently on the initial events in the viral life cycle: 1) characterizing MNV entry into murine macrophages and dendritic cells in vitro, 2) determining the mechanism of MNV transcytosis across intestinal epithelial monolayers in vitro, 3) identifying the MNV receptor(s), and 4) defining the receptor binding site on the MNV capsid.
During the past year, we have identified a role for sialic acid and specific gangliosides, in particular GD1a, as attachment factors for MNV-1 binding to the murine macrophage cell line RAW 264.7. Current studies are aimed at broadening these findings to other MNV strains and primary murine macrophages. Furthermore, we determined that MNV-1 does not require acidification of endosomal vesicles to infect Mf and DCs. Ongoing studies are looking at the role of lipid rafts and caveosomes in viral entry. In addition, we have just solved the crystal structure of the MNV-1 P domain, which is the surface exposed portion of the viral capsid. We are now beginning structure function analysis of the P domain to identify receptor binding sites. Our ability to isolate large amounts of P domain also enables us to begin screens to identify antiviral compounds which block virus binding to cells and develop new strategies for norovirus control.