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Journal of Virology, November 2006, p. 10372-10381, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00809-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Pathogenesis of a Genogroup II Human Norovirus in Gnotobiotic Pigs

Sonia Cheetham,1 Menira Souza,1 Tea Meulia,2 Sheila Grimes,3 Myung Guk Han,1 and Linda J. Saif1*

Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, Ohio 44691,1 Molecular and Cellular Imaging Center, Ohio Agricultural Research and Development Center, Wooster, Ohio,2 Animal Disease Diagnostic Laboratory, Ohio Department of Agriculture, Reynoldsburg, Ohio3

Received 19 April 2006/ Accepted 3 August 2006

We evaluated the gnotobiotic (Gn) pig as a model to study the pathogenesis of human norovirus (HuNoV) and to determine the target cells for viral replication. Sixty-five Gn pigs were inoculated with fecal filtrates of the NoV/GII/4/HS66/2001/US strain or with pig-passaged intestinal contents (IC) and euthanized acutely (n = 43) or after convalescence (n = 22). Age-matched Gn piglets (n = 14) served as mock-inoculated controls. Seventy-four percent (48/65) of the inoculated animals developed mild diarrhea compared to 0 of 14 controls. Pigs from postinoculation days (PID) 1 to 4 tested positive for HuNoV by reverse transcription-PCR of rectal swab fluids (29/65) and IC (9/43) and by antigen (Ag) enzyme-linked immunosorbent assay (ELISA) using antiserum to virus-like particles of HuNoV GII/4. No control pigs were positive. Histopathologic examination showed mild lesions in the proximal small intestine of only one pig (1/7). Seroconversion after PID 21 was detected by antibody ELISA in 13 of 22 virus-inoculated pigs (titers, 1:20 to 1:200) but not in controls. Immunofluorescent microscopy using a monoclonal antibody to HuNoV GII capsid revealed patchy infection of duodenal and jejunal enterocytes of 18 of 31 HuNoV-inoculated pigs with a few stained cells in the ileum and no immunofluorescence (IF) in mock-inoculated controls. Immunofluorescent detection of the viral nonstructural N-terminal protein antigen in enterocytes confirmed translation. Transmission electron microscopy of intestines from HuNoV-inoculated pigs showed disrupted enterocytes, with cytoplasmic membrane vesicles containing calicivirus-like particles of 25 to 40 nm in diameter. In summary, serial passage of HuNoV in pigs, with occurrence of mild diarrhea and shedding, and immunofluorescent detection of the HuNoV structural and nonstructural proteins in enterocytes confirm HuNoV replication in Gn pigs.

* Corresponding author. Mailing address: Food Animal Health Research Program, Ohio Agricultural Research and Development Center, The Ohio State University, 1680 Madison Avenue, Wooster, OH 44691. Phone: (330) 263-3744. Fax: (330) 263-3677. E-mail: saif.2{at}osu.edu.

Journal of Virology, November 2006, p. 10372-10381, Vol. 80, No. 21
0022-538X/06/$08.00+0     doi:10.1128/JVI.00809-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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