Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1994 Oct;68(10):6458–6465. doi: 10.1128/jvi.68.10.6458-6465.1994

Association of the reovirus S1 gene with serotype 3-induced biliary atresia in mice.

G A Wilson 1, L A Morrison 1, B N Fields 1
PMCID: PMC237066  PMID: 8083983

Abstract

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 (LD50s) 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 biliary atresia. The capacity to cause biliary atresia was not related to the capacity to cause lethal infection, however, because the LD50s of T3 Abney and T3 clone 31 were grossly disparate. Examination of liver and bile duct tissues revealed histopathologic evidence of biliary atresia and hepatic necrosis in T3 Abney-infected mice but not in mice inoculated with a T3 strain of similar virulence or with the hepatotropic 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 coinfection with T3 Abney and T1 Lang indicated a strong association of the hepatobiliary disease-producing phenotype with the T3 Abney S1 gene, which encodes the viral cell attachment protein, sigma 1. Amino acid residues within the sigma 1 protein that were unique to disease-producing T3 strains were identified by comparative sequence analysis. Specific changes exist within two regions of the protein, one of which is thought to be involved in binding to host cell receptors. We hypothesize that changes within this region of the protein are important in determining the tropism of this virus for bile-ductular epithelium.

Full text

PDF
6458

Images in this article

6461Image
on p.6461
6461Image
on p.6461

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahmed R., Fields B. N. Role of the S4 gene in the establishment of persistent reovirus infection in L cells. Cell. 1982 Mar;28(3):605–612. doi: 10.1016/0092-8674(82)90215-x. [DOI] [PubMed] [Google Scholar]
  2. Bangaru B., Morecki R., Glaser J. H., Gartner L. M., Horwitz M. S. Comparative studies of biliary atresia in the human newborn and reovirus-induced cholangitis in weanling mice. Lab Invest. 1980 Nov;43(5):456–462. [PubMed] [Google Scholar]
  3. Bassel-Duby R., Spriggs D. R., Tyler K. L., Fields B. N. Identification of attenuating mutations on the reovirus type 3 S1 double-stranded RNA segment with a rapid sequencing technique. J Virol. 1986 Oct;60(1):64–67. doi: 10.1128/jvi.60.1.64-67.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bodkin D. K., Fields B. N. Growth and survival of reovirus in intestinal tissue: role of the L2 and S1 genes. J Virol. 1989 Mar;63(3):1188–1193. doi: 10.1128/jvi.63.3.1188-1193.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bruck C., Co M. S., Slaoui M., Gaulton G. N., Smith T., Fields B. N., Mullins J. I., Greene M. I. Nucleic acid sequence of an internal image-bearing monoclonal anti-idiotype and its comparison to the sequence of the external antigen. Proc Natl Acad Sci U S A. 1986 Sep;83(17):6578–6582. doi: 10.1073/pnas.83.17.6578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dermody T. S., Nibert M. L., Bassel-Duby R., Fields B. N. A sigma 1 region important for hemagglutination by serotype 3 reovirus strains. J Virol. 1990 Oct;64(10):5173–5176. doi: 10.1128/jvi.64.10.5173-5176.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dermody T. S., Nibert M. L., Bassel-Duby R., Fields B. N. Sequence diversity in S1 genes and S1 translation products of 11 serotype 3 reovirus strains. J Virol. 1990 Oct;64(10):4842–4850. doi: 10.1128/jvi.64.10.4842-4850.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Drayna D., Fields B. N. Genetic studies on the mechanism of chemical and physical inactivation of reovirus. J Gen Virol. 1982 Nov;63(Pt 1):149–159. doi: 10.1099/0022-1317-63-1-149. [DOI] [PubMed] [Google Scholar]
  9. Duncan R., Horne D., Cashdollar L. W., Joklik W. K., Lee P. W. Identification of conserved domains in the cell attachment proteins of the three serotypes of reovirus. Virology. 1990 Feb;174(2):399–409. doi: 10.1016/0042-6822(90)90093-7. [DOI] [PubMed] [Google Scholar]
  10. Duncan R., Horne D., Strong J. E., Leone G., Pon R. T., Yeung M. C., Lee P. W. Conformational and functional analysis of the C-terminal globular head of the reovirus cell attachment protein. Virology. 1991 Jun;182(2):810–819. doi: 10.1016/0042-6822(91)90622-i. [DOI] [PubMed] [Google Scholar]
  11. Furlong D. B., Nibert M. L., Fields B. N. Sigma 1 protein of mammalian reoviruses extends from the surfaces of viral particles. J Virol. 1988 Jan;62(1):246–256. doi: 10.1128/jvi.62.1.246-256.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Glaser J. H., Morecki R. Reovirus type 3 and neonatal cholestasis. Semin Liver Dis. 1987 May;7(2):100–107. doi: 10.1055/s-2008-1040569. [DOI] [PubMed] [Google Scholar]
  13. Hrdy D. B., Rosen L., Fields B. N. Polymorphism of the migration of double-stranded RNA genome segments of reovirus isolates from humans, cattle, and mice. J Virol. 1979 Jul;31(1):104–111. doi: 10.1128/jvi.31.1.104-111.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hrdy D. B., Rubin D. H., Fields B. N. Molecular basis of reovirus neurovirulence: role of the M2 gene in avirulence. Proc Natl Acad Sci U S A. 1982 Feb;79(4):1298–1302. doi: 10.1073/pnas.79.4.1298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kauffman R. S., Wolf J. L., Finberg R., Trier J. S., Fields B. N. The sigma 1 protein determines the extent of spread of reovirus from the gastrointestinal tract of mice. Virology. 1983 Jan 30;124(2):403–410. doi: 10.1016/0042-6822(83)90356-2. [DOI] [PubMed] [Google Scholar]
  16. Lee P. W., Hayes E. C., Joklik W. K. Characterization of anti-reovirus immunoglobulins secreted by cloned hybridoma cell lines. Virology. 1981 Jan 15;108(1):134–146. doi: 10.1016/0042-6822(81)90533-x. [DOI] [PubMed] [Google Scholar]
  17. Lee P. W., Hayes E. C., Joklik W. K. Protein sigma 1 is the reovirus cell attachment protein. Virology. 1981 Jan 15;108(1):156–163. doi: 10.1016/0042-6822(81)90535-3. [DOI] [PubMed] [Google Scholar]
  18. Matoba Y., Sherry B., Fields B. N., Smith T. W. Identification of the viral genes responsible for growth of strains of reovirus in cultured mouse heart cells. J Clin Invest. 1991 May;87(5):1628–1633. doi: 10.1172/JCI115177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Morrison L. A., Sidman R. L., Fields B. N. Direct spread of reovirus from the intestinal lumen to the central nervous system through vagal autonomic nerve fibers. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3852–3856. doi: 10.1073/pnas.88.9.3852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Nagata L., Masri S. A., Pon R. T., Lee P. W. Analysis of functional domains on reovirus cell attachment protein sigma 1 using cloned S1 gene deletion mutants. Virology. 1987 Sep;160(1):162–168. doi: 10.1016/0042-6822(87)90056-0. [DOI] [PubMed] [Google Scholar]
  21. Nibert M. L., Dermody T. S., Fields B. N. Structure of the reovirus cell-attachment protein: a model for the domain organization of sigma 1. J Virol. 1990 Jun;64(6):2976–2989. doi: 10.1128/jvi.64.6.2976-2989.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nibert M. L., Fields B. N. A carboxy-terminal fragment of protein mu 1/mu 1C is present in infectious subvirion particles of mammalian reoviruses and is proposed to have a role in penetration. J Virol. 1992 Nov;66(11):6408–6418. doi: 10.1128/jvi.66.11.6408-6418.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Papadimitriou J. M. The biliary tract in acute murine reovirus 3 infection. Light and electron microscopic study. Am J Pathol. 1968 Mar;52(3):595–611. [PMC free article] [PubMed] [Google Scholar]
  24. Phillips P. A., Keast D., Papadimitriou J. M., Walters M. N., Stanley N. F. Chronic obstructive jaundice induced by Reovirus type 3 in weanling mice. Pathology. 1969 Jul;1(3):193–203. doi: 10.3109/00313026909071296. [DOI] [PubMed] [Google Scholar]
  25. ROSEN L., ABINANTI F. R., HOVIS J. F. Further observations on the natural infection of cattle with reoviruses. Am J Hyg. 1963 Jan;77:38–48. doi: 10.1093/oxfordjournals.aje.a120294. [DOI] [PubMed] [Google Scholar]
  26. ROSEN L., ABINANTI F. R. Natural and experimental infection of catle with human types of reoviruses. Am J Hyg. 1960 Mar;71:250–257. doi: 10.1093/oxfordjournals.aje.a120108. [DOI] [PubMed] [Google Scholar]
  27. ROSEN L., HOVIS J. F., MASTROTA F. M., BELL J. A., HUEBNER R. J. Observations on a newly recognized virus (Abney) of the reovirus family. Am J Hyg. 1960 Mar;71:258–265. doi: 10.1093/oxfordjournals.aje.a120109. [DOI] [PubMed] [Google Scholar]
  28. Ramig R. F., Cross R. K., Fields B. N. Genome RNAs and polypeptides of reovirus serotypes 1, 2, and 3. J Virol. 1977 Jun;22(3):726–733. doi: 10.1128/jvi.22.3.726-733.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Rubin D. H., Costello T., Witzleben C. L., Greene M. I. Transport of infectious reovirus into bile: class II major histocompatibility antigen-bearing cells determine reovirus transport. J Virol. 1987 Oct;61(10):3222–3226. doi: 10.1128/jvi.61.10.3222-3226.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rubin D. H., Fields B. N. Molecular basis of reovirus virulence. Role of the M2 gene. J Exp Med. 1980 Oct 1;152(4):853–868. doi: 10.1084/jem.152.4.853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. STANLEY N. F., DORMAN D. C., PONSFORD J. Studies on the pathogenesis of a hitherto undescribed virus (hepato-encephalomyelitis) producing unusual symptoms in suckling mice. Aust J Exp Biol Med Sci. 1953 Apr;31(2):147–159. doi: 10.1038/icb.1953.18. [DOI] [PubMed] [Google Scholar]
  32. Schiff L. A., Nibert M. L., Co M. S., Brown E. G., Fields B. N. Distinct binding sites for zinc and double-stranded RNA in the reovirus outer capsid protein sigma 3. Mol Cell Biol. 1988 Jan;8(1):273–283. doi: 10.1128/mcb.8.1.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sharpe A. H., Ramig R. F., Mustoe T. A., Fields B. N. A genetic map of reovirus. 1. Correlation of genome RNAs between serotypes 1, 2, and 3. Virology. 1978 Jan;84(1):63–74. doi: 10.1016/0042-6822(78)90218-0. [DOI] [PubMed] [Google Scholar]
  34. Smith R. E., Zweerink H. J., Joklik W. K. Polypeptide components of virions, top component and cores of reovirus type 3. Virology. 1969 Dec;39(4):791–810. doi: 10.1016/0042-6822(69)90017-8. [DOI] [PubMed] [Google Scholar]
  35. Spriggs D. R., Bronson R. T., Fields B. N. Hemagglutinin variants of reovirus type 3 have altered central nervous system tropism. Science. 1983 Apr 29;220(4596):505–507. doi: 10.1126/science.6301010. [DOI] [PubMed] [Google Scholar]
  36. Spriggs D. R., Fields B. N. Attenuated reovirus type 3 strains generated by selection of haemagglutinin antigenic variants. Nature. 1982 May 6;297(5861):68–70. doi: 10.1038/297068a0. [DOI] [PubMed] [Google Scholar]
  37. Stanley N. F. Reoviruses. Br Med Bull. 1967 May;23(2):150–154. doi: 10.1093/oxfordjournals.bmb.a070536. [DOI] [PubMed] [Google Scholar]
  38. Turner D. L., Duncan R., Lee P. W. Site-directed mutagenesis of the C-terminal portion of reovirus protein sigma 1: evidence for a conformation-dependent receptor binding domain. Virology. 1992 Jan;186(1):219–227. doi: 10.1016/0042-6822(92)90076-2. [DOI] [PubMed] [Google Scholar]
  39. Tyler K. L., Bronson R. T., Byers K. B., Fields B. Molecular basis of viral neurotropism: experimental reovirus infection. Neurology. 1985 Jan;35(1):88–92. doi: 10.1212/wnl.35.1.88. [DOI] [PubMed] [Google Scholar]
  40. Tyler K. L., McPhee D. A., Fields B. N. Distinct pathways of viral spread in the host determined by reovirus S1 gene segment. Science. 1986 Aug 15;233(4765):770–774. doi: 10.1126/science.3016895. [DOI] [PubMed] [Google Scholar]
  41. Virgin H. W., 4th, Tyler K. L. Role of immune cells in protection against and control of reovirus infection in neonatal mice. J Virol. 1991 Oct;65(10):5157–5164. doi: 10.1128/jvi.65.10.5157-5164.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. WALTERS M. N., JOSKE R. A., LEAK P. J., STANLEY N. F. MURINE INFECTION WITH REOVIRUS: I. PATHOLOGY OF THE ACUTE PHASE. Br J Exp Pathol. 1963 Aug;44:427–436. [PMC free article] [PubMed] [Google Scholar]
  43. Weiner H. L., Drayna D., Averill D. R., Jr, Fields B. N. Molecular basis of reovirus virulence: role of the S1 gene. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5744–5748. doi: 10.1073/pnas.74.12.5744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Weiner H. L., Powers M. L., Fields B. N. Absolute linkage of virulence and central nervous system cell tropism of reoviruses to viral hemagglutinin. J Infect Dis. 1980 May;141(5):609–616. doi: 10.1093/infdis/141.5.609. [DOI] [PubMed] [Google Scholar]
  45. Williams W. V., Guy H. R., Rubin D. H., Robey F., Myers J. N., Kieber-Emmons T., Weiner D. B., Greene M. I. Sequences of the cell-attachment sites of reovirus type 3 and its anti-idiotypic/antireceptor antibody: modeling of their three-dimensional structures. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6488–6492. doi: 10.1073/pnas.85.17.6488. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES