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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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Categories: 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 8

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Binding of T3SA– and T3SA+ to L cells and Mz-Cha-1 cells. L cells (a–d) ...
Binding of T3SA– and T3SA+ to L cells and Mz-Cha-1 cells. L cells (a–d) or Mz-Cha-1 biliary epithelial cells (e–h) were either mock-treated (a, b, e, and f) or treated with C. perfringens neuraminidase to remove cell-surface terminal sialic acid residues (c, d, g, and h). Cells were incubated with 0 (black line), 103 (red line), 104 (green line), or 105 (blue line) particles per cell of T3SA– (a, c, e, and g) or T3SA+ (b, d, f, and h). Unbound virus was removed, and bound virus on the cell surface was detected using rabbit anti-reovirus serum followed by phycoerythrin-labeled goat anti-rabbit Fab’s. Histograms represent data gated on total live-cell populations. Shown are representative histograms from one experiment (L cells) or two experiments (Mz-Cha-1 cells). Preimmune rabbit serum caused less than a threefold increase in fluorescence in the presence of 106 particles per cell of virus (data not shown).
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