Text Image: UM Medical School: Graduate Program in Immunology
Text Image: Faculty

Christiane Wobus, Ph.D.
Assistant Professor,
Department of Microbiology and Immunology
cwobus@umich.edu


Research Interests

Mechanisms of norovirus – host interactions with macrophages, dendritic cells, and the gastrointestinal tract


Research Activity

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 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.  Current studies in the lab are focused on: 1) mechanisms of MNV transcytosis across intestinal epithelial monolayers in vitro and in vivo, 2) the role of dendritic cells during MNV infection in vivo, 3) identification of MNV receptor(s), 4) defining the receptor binding site(s) on the MNV capsid, and 5) investigating the role of cellular deubiquitinases during MNV infection in macrophages and dendritic cells.

We are also starting to expand our studies to human noroviruses using the currently available techniques (e.g. replicon system, virus-like particles) and develop methods to cultivate these viruses. Future topics for graduate students with an interest in immunology, will include (in no particular order):

1. The role of dendritic cells during MNV pathogenesis

Ongoing studies in the lab have shown that DCs are critical for MNV spread to the mesenteric lymph node and to extraintestinal sites. We like to determine the subtypes of dendritic cells infected and the specific role during pathogenesis, including whether MNV infects its host via transepithelial dendrites of dendritic cells reaching through the intestinal epithelium to sample the intestinal lumen.

2. Mechanisms of norovirus transcytosis across the intestinal epithelium

Ongoing work in the laboratory has shown that microfold (M) cells within the intestinal epithelium are critical during MNV and reovirus pathogenesis.  Furthermore, MNV can cross an intestinal epithelial monolayer in vitro via M-like cells without disrupting tight junctions by an intracellular endocytic pathway called transcytosis. Our goal is to identify cellular factors required during this process and to expand the in vitro studies to include studies with human norovirus virus-like particles (a non-infectious form of the virus comprised only of the virus capsid).

3. The role of cellular deubiquitinases during norovirus infection

The ubiquitin system plays a fundamental role during many cellular processes, including cytokine signaling. Deubiquitinases are a critical regulator of the ubiquitin cycle but relatively little is known regarding their functions.  We have discovered a small molecule inhibitor of a select set of cellular deubiquitinases that inhibits replication of MNV and the human norovirus Norwalk virus. Ongoing studies are focused on identifying the complete set of target proteins targeted by the small molecule inhibitor, the anti-viral mechanism of action of the small molecule, and the function of these deubiquitinases in macrophages and dendritic cells.

 

Representative Recent Publications

Taube, S*., Kolawole, A.O.*, Höhne, M., Wilkinson, J.E., Handley, S.A., Perry, J.W., Thackray, LB., Akkina, R., Wobus, C.E. (2013) A Mouse Model for Human Norovirus. mBIO (accepted for publication)

Perry, J.W., Ahmed, M., Chang, K.-O., Donato, N.J., Showalter, H.D., and Wobus, C.E. (2012) Antiviral Activity of a Small Molecule Deubiquitinase Inhibitor Occurs via Induction of the Unfolded Protein Response. PLoS Pathogens 8:e1002783.

Taube, S., Perry, J. W., McGreevy, E., Yetming, K., Perkins, C., Henderson, K., Wobus, C. E. (2012) Murine noroviruses (MNV) bind glycolipid and glycoprotein attachment receptors in a strain-dependent manner. Journal of Virology 86:5584-93.

Kim, Y.G., Park, J.H., Reimer, T., Baker, D.P., Kawai, T., Kumar, H., Akira, S., Wobus C., Núñez, G. (2011) Viral infection augments nod1/2 signaling to potentiate lethality associated with secondary bacterial infections. Cell Host Microbe 9, 496-507

Taube, S., Jiang, M., and Wobus, C.E. (2010) Glycosphingolipids as Receptors for Non-Enveloped Viruses.  Viruses 2, 1011-1049 (invited review)

Perry, J. and Wobus, C. E. (2010) Endocytosis of Murine Norovirus 1 (MNV-1) into murine macrophages is dependent on dynamin II and cholesterol. Journal of Virology 84, 6163–6176

Taube, S., Rubin, J. R., Katpally, U., Smith, T. S., Kendall, A., Stuckey, J. A., and Wobus, C. E. (2010) High Resolution X-Ray Structure and Functional Analysis of the Murine Norovirus (MNV)-1 Capsid Protein Protruding (P) Domain. Journal of Virology 84, 5695-705

Perry, J., Taube, S., Wobus, C. E. (2009) Murine Norovirus-1 entry into permissive macrophages and dendritic cells is pH-independent. Virus Research 43, 125-9.

Taube, S., Perry, J. W., Yetming, K., Patel, S. P., Auble, H., Shu, L., Nawar, H. F., Lee, C. H., Connell, T. D., Shayman, J., Wobus, C. E. (2009) Ganglioside-linked terminal sialic acid moieties on murine macrophages function as attachment receptors for Murine Noroviruses (MNV). Journal of Virology 83, 4092-101. PMID: 19244326

 

 


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