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Utilization of sialic acid as a coreceptor is required for reovirus-induced biliary disease
Erik S. Barton, … , J. Denise Wetzel, Terence S. Dermody
Erik S. Barton, … , J. Denise Wetzel, Terence S. Dermody
Published June 15, 2003
Citation Information: J Clin Invest. 2003;111(12):1823-1833. https://doi.org/10.1172/JCI16303.
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Article Virology

Utilization of sialic acid as a coreceptor is required for reovirus-induced biliary disease

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Abstract

Infection of neonatal mice with some reovirus strains produces a disease similar to infantile biliary atresia, but previous attempts to correlate reovirus infection with this disease have yielded conflicting results. We used isogenic reovirus strains T3SA– and T3SA+, which differ solely in the capacity to bind sialic acid as a coreceptor, to define the role of sialic acid in reovirus encephalitis and biliary tract infection in mice. Growth in the intestine was equivalent for both strains following peroral inoculation. However, T3SA+ spread more rapidly from the intestine to distant sites and replicated to higher titers in spleen, liver, and brain. Strikingly, mice infected with T3SA+ but not T3SA– developed steatorrhea and bilirubinemia. Liver tissue from mice infected with T3SA+ demonstrated intense inflammation focused at intrahepatic bile ducts, pathology analogous to that found in biliary atresia in humans, and high levels of T3SA+ antigen in bile duct epithelial cells. T3SA+ bound 100-fold more efficiently than T3SA– to human cholangiocarcinoma cells. These observations suggest that the carbohydrate-binding specificity of a virus can dramatically alter disease in the host and highlight the need for epidemiologic studies focusing on infection by sialic acid–binding reovirus strains as a possible contributor to the pathogenesis of neonatal biliary atresia.

Authors

Erik S. Barton, Bryan E. Youree, Daniel H. Ebert, J. Craig Forrest, Jodi L. Connolly, Tibor Valyi-Nagy, Kay Washington, J. Denise Wetzel, Terence S. Dermody

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Figure 7

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Immunohistochemical localization of reovirus antigen in bile duct epithe...
Immunohistochemical localization of reovirus antigen in bile duct epithelial cells. ND4 Swiss Webster mice, 2–3 days old, were inoculated perorally with 2.5 × 103 PFU of either T3SA– (a and b) or T3SA+ (c and d). Six days after inoculation, liver tissue was harvested, embedded in paraffin, thin-sectioned, and stained for reovirus antigen using rabbit anti-reovirus serum and horseradish peroxidase. Dark brown staining indicates reovirus antigen. Sections from approximately ten mice infected with each virus were examined and showed qualitatively similar results. Photomicrographs were prepared at ×400 final magnification. Representative sections from two separate animals are shown.
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