Utilization of sialic acid as a coreceptor is required for reovirus-induced biliary disease.
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.
Barton
Erik S
ES
Department of Microbiology and Immunology and Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Youree
Bryan E
BE
Ebert
Daniel H
DH
Forrest
J Craig
JC
Connolly
Jodi L
JL
Valyi-Nagy
Tibor
T
Washington
Kay
K
Wetzel
J Denise
JD
Dermody
Terence S
TS
D000818:Animals; D000831:Animals, Newborn; D000956:Antigens, Viral / Q000378:metabolism; D001652:Bile Ducts / Q000821:virology; D001656:Biliary Atresia / Q000209:etiology* / Q000503:physiopathology / Q000821:virology; D002460:Cell Line; D018792:Encephalitis, Viral / Q000209:etiology / Q000503:physiopathology / Q000821:virology; D005838:Genotype; D006801:Humans; D012089:Mammalian orthoreovirus 3 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D051379:Mice; D019158:N-Acetylneuraminic Acid / Q000502:physiology*; D010641:Phenotype; D011991:Receptors, Virus / Q000502:physiology*; D012088:Reoviridae Infections / Q000150:complications* / Q000503:physiopathology / Q000821:virology; D014407:Tumor Cells, Cultured; D014774:Virulence / Q000235:genetics / Q000502:physiology; D014779:Virus Replication
D000956:Antigens, Viral; D011991:Receptors, Virus; D019158:N-Acetylneuraminic Acid