ASSOCIATION OF THE REOVIRUS S1 GENE WITH SEROTYPE 3-INDUCED BILIARY ATRESIA IN MICE

A panel of serotype 3 (T3) reovirus strains was screened to determine their relative capacities to cause lethal infection and hepatobiliary disease following peroral inoculation in newborn mice. A wide range of 50% lethal doses (LD(50)s) was apparent after peroral inoculation of the different virus strains. Two of the strains, T3 Abney and T3 clone 31, caused mice to develop the oily fur syndrome associated with bili ary atresia. The capacity to cause biliary atresia was not related to the capacity to cause lethal infection, however, because the LD(50)s o f T3 Abney and T3 clone 31 were grossly disparate. Examination of live r and bile duct tissues revealed histopathologic evidence of biliary a tresia and hepatic necrosis in T3 Abney-infected mice but not in mice inoculated with a T3 strain of similar virulence or with the hepatotro pic T1 Lang strain. The consistency with which T3 Abney-infected mice developed biliary atresia-associated oily fur syndrome permitted us to determine the viral genetic basis of reovirus-induced biliary atresia . Analysis of reassortant viruses isolated from an in vitro coinfectio n with T3 Abney and T1 Lang indicated a strong association of the hepa tobiliary disease-producing phenotype,vith the T3 Abney S1 gene, which encodes the viral cell attachment protein, sigma 1. Amino acid residu es within the al protein that were unique to disease-producing T3 stra ins were identified by comparative sequence analysis. Specific changes exist within two regions of the protein, one of which is thought to b e involved in binding to host cell receptors. We hypothesize that chan ges within this region of the protein are important in determining the tropism of this virus for bile-ductular epithelium.