Christiane Wobus , Ph.D.
Assistant Professor,
Department of Microbiology and Immunology

cwobus@umich.edu

Research Interests:

My research interest is in norovirus - host cell interaction in vitro
and in vivo. Our focus in the lab is to understand the mechanisms that
lead to murine norovirus infection of macrophages and dendritic cells
and the consequences of this infection for the host. In addition, we
are initiating studies of norovirus interaction at the mucosal surface
of the gut and the interplay between virus, host and the microbiome in
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 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. Current studies in lab are focused on: 1) MNV entry into murine macrophages and dendritic cells in vitro , 2) 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.

In the future, I plan on expanding our studies on MNV transcytosis to investigate norovirus – host interaction at the mucosal surface of the gastrointestinal tract. While some of these studies will utilize our epithelial monolayer system in vitro the focus will be on events occurring in vivo . Future topics for graduate students with an interest in immunology, will include (in no particular order):

•  elucidating the immunological consequences of MNV infection of dendritic cells

Human norovirus infection leads to short-term immunity (up to 1 year) but the reasons for this are unclear. Therefore, we like to determine whether MNV infection of DCs changes cell surface markers and whether that influences DC interaction with T and B cells. While we and others have been unable to productively infect DCs with human noroviruses, viral infection is not a prerequisite for the induction of changes in cell surface expression of proteins. Therefore, similar studies would also be extended to human noroviruses.

•  immunological consequences of MNV interaction with intestinal epithelial cells and the role of intestinal dendritic cells and macrophages in MNV infection

Human norovirus disease is typically short and self-limiting (1-2 days) in individuals with a healthy immune system. The limited histopathological changes observed in intestinal biopsies and extremely spotty and limited detection of virus by immunohistochemistry does not explain the severity of disease. A leading hypothesis in the field is that disease is mediated by a cytokine “storm”. However, nothing is known about the cytokine response or which cell types mediate this response. Again, while the initial studies would focus on MNV, the idea is to extend these studies to human noroviruses.

•  immunological consequences of disrupted commensal bacterial flora after MNV infection

Bacterial gastroenteritis leads to mucosal damage and disruption of the commensal flora and develops into post-infectious irritable bowel syndrome (PI-IBS) in a subset of patients. Whether viral gastroenteritis can also be a factor in PI-IBS is unknown. We have preliminary data that MNV infection changes the microbiota in the intestinal tract.

•  mechanism of action and role of T regulatory cells in persistent vs. acute MNV infection

T cells are important for clearance of MNV infection. However many MNV strains establish a persistent infection in the presence of a functioning immune system. T regulatory cells have been shown to play a role in some cases of viral persistence but the role during persistent MNV infection remains unknown.

Representative Recent Publications:

Katpally, U., Wobus, C. E., Dryden, K., Virgin, H. W. 4th, Smith, T. J.
(2008) The Structure of Antibody Neutralized Murine Norovirus and
Unexpected Differences to Virus Like Particles. Journal of Virology 82,
2079-88

Thackray, L. B., Wobus, C. E., Chachu, K. A., Liu, B., Alegre, E. R.,
Henderson, K. S., Kelley, S. T., Virgin, H. W. 4th (2007) Murine
noroviruses comprising a single genogroup exhibit biological diversity
despite limited sequence divergence. Journal of Virology 81,
10460-10473.

Ward, V. K., McCormick, C. J., Clarke, I. N., Salim, O., Wobus, C. E.,
Thackray, L. B., Virgin, H. W. 4th, Lambden, P. R. (2007) Recovery of
infectious murine norovirus using pol II-driven expression of
full-length cDNA. PNAS 104, 11050-11055.

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.

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.)