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Journal of Virology, April 2007, p. 3251-3263, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02096-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Murine Norovirus 1 Infection Is Associated with Histopathological Changes in Immunocompetent Hosts, but Clinical Disease Is Prevented by STAT1-Dependent Interferon Responses

Shannon M. Mumphrey,^1, Harish Changotra,^1, Tara N. Moore,¹ Ellen R. Heimann-Nichols,¹ Christiane E. Wobus,² Michael J. Reilly,¹ Mana Moghadamfalahi,³ Deepti Shukla,³ and Stephanie M. Karst^1*

Center for Molecular and Tumor Virology, Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932,¹ Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110,² Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932³

Received 25 September 2006/ Accepted 3 January 2007

Human noroviruses are the major cause of nonbacterial epidemic gastroenteritis worldwide. However, little is known regarding their pathogenesis or the immune responses that control them because until recently there has been no small animal model or cell culture system of norovirus infection. We recently reported the discovery of the first murine norovirus, murine norovirus 1 (MNV-1), and its cultivation in macrophages and dendritic cells in vitro. We further defined interferon receptors and the STAT-1 molecule as critical in both resistance to MNV-1-induced disease in vivo and control of virus growth in vitro. To date, neither histopathological changes upon infection nor viral replication in wild-type mice has been shown. Here we extend our studies to demonstrate that MNV-1 replicates and rapidly disseminates to various tissues in immunocompetent mice and that infection is restricted by STAT1-dependent interferon responses at the levels of viral replication and virus dissemination. Infection of wild-type mice is associated with histopathological alterations in the intestine (mild inflammation) and the spleen (red pulp hypertrophy and white pulp activation); viral dissemination to the spleen, liver, lung, and lymph nodes; and low-level persistent infection in the spleen. STAT-1 inhibits viral replication in the intestine, prevents virus-induced apoptosis of intestinal cells and splenocytes, and limits viral dissemination to peripheral tissues. These findings demonstrate that murine norovirus infection of wild-type mice is associated with initial enteric seeding and subsequent extraintestinal spread, and they provide mechanistic evidence of the role of STAT-1 in controlling clinical norovirus-induced disease.

Published ahead of print on 17 January 2007.

S.M.M. and H.C. contributed equally to this work.

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