Faculty

Mechanisms of norovirus entry into host cells in vitro and in vivo

    Noroviruses, members of the Caliciviridae family, primarily infect humans but also infect pigs, cattle and mice.  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 where crowds gather. Due to the explosiveness of the outbreaks and new strains on the rise, these viruses frequently appear in the popular press where they are often called “stomach bugs”.  (For a recent local story go to: Norovirus cases on rise). 
 
   However, despite the importance for public health, 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.  Even knowledge of fundamental issues such as the viral life cycle and interactions with their host is lacking.  Such information however is crucial in understanding how noroviruses cause disease and in developing antiviral therapies for these common agents of gastroenteritis.

    We recently discovered the first murine norovirus (MNV-1) (Karst et al., 2003), and developed the first in vitro culture system for a norovirus (Wobus et al., 2004).  This gives my lab a unique system to address some of the outstanding questions and begin a detailed analysis of different aspects of norovirus biology.  Of particular interest to me are the early steps (receptor binding, entry) in the viral life cycle because they are major factors in determining species or tissue specificity, virulence and ultimately the outcome of a virus infection. Therefore, the focus of my lab is on studying early steps in the viral life cycle (mechanisms of viral entry into host cells) and mechanisms governing virus-host interactions in vitro and in vivo.

    In addition, virus-receptor interaction and virus entry have become attractive targets for antiviral therapies.  Therefore, we are interested in identifying new antiviral compounds and develop new strategies for norovirus control. 

Selected Publications: 

    Mumphrey, S. M., Changotra, H., Moore, T. N., Heimann-Nichols, E. R., Wobus, C. E., Reilly, M. J., Moghadamfalahi, M., Shukla, D., Karst, S. M. (2007) Murine norovirus 1 infection is associated with histopathological changes in immunocompetent hosts but clinical disease is prevented by STAT1-dependent interferon responses. Journal of Virology 2007 Jan 17; [Epub ahead of print]

    Ward J. M., Wobus, C. E., Thackray, L. B., Erexson, C. R., Faucette, L. J., Belliot, G., Barron, E. L., Sosnovtsev, S. V., Green, K. Y. (2006) Pathology of immunodeficient mice with naturally occurring murine norovirus infection. Toxicological Patholology 34, 708-15.

    Sosnovtsev, S. V., Belliot, G., Chang, K. O., Prikhodko, V. G., Thackray, L. B., Wobus, C. E., Karst, S. M., Virgin, H. W., and Green, K. Y. (2006) Cleavage map and proteolytic processing of the murine norovirus nonstructural polyprotein in infected cells. Journal of Virology 80, 7816-31.

    Daughenbaugh, K. F., Wobus, C. E., Hardy, M. E. (2006) VPg of murine norovirus binds translation initiation factors in infected cells.  Virology Journal 3, 33.

    Wobus C. E., Thackray L. B., Virgin H. W. 4th (2006) Murine norovirus: a model system to study norovirus biology and pathogenesis. Journal of Virology 80, 5104-12.

    Hsu, C.C., Wobus, C. E., Steffen, E. K., Riley, L. K., Livingston, R. S. (2005) Development of a microsphere-based serologic multiplexed fluorescent immunoassay and reverse transcriptase-PCR assay to detect Murine Norovirus 1 (MNV-1) infection in mice. Clinical and Diagnostic Laboratory Immunology 12, 1145-51.

    Wobus, C. E., Karst S. M., Thackray, L. B., Chang, K.-O., Sosnovstev S., Belliot, G., Krug, A., Mackenzie, J. M., Green., K. Y., Virgin, H. W. (2004) Replication of a norovirus in culture reveals a tropism for dendritic cells and macrophages.  PLOS Biology 2. e432.

     Karst S. M.*, Wobus, C. E.*, Lay, M., Davidson, J., Virgin, H. W. (2003) STAT-1 dependent innate immunity to a Norwalk-like virus.  Science 299, 1575-1578. (* both authors contributed equally)