title: Contributions of the lymphocytic choriomeningitis virus glycoprotein and polymerase to strain-specific differences in murine liver pathogenicity.
abstract: Hepatic involvement is commonly observed in arenavirus infections, but the viral determinants of liver disease are only partially understood. Here we exploited newly developed reverse-genetic techniques with Lymphocytic choriomeningitis virus (LCMV), the prototype arenavirus, to address specifically the contribution of the viral glycoprotein (GP) to liver pathogenicity. It is well established that strain WE, but not ARM, causes hepatitis in mice. We found that this property correlated with the superior capacity of WE to propagate in cultured macrophages and hepatocyte-derived cells. In mice, the ability to establish prolonged viraemia allowed the virus to propagate from initially infected Kupffer cells in the liver to neighbouring hepatocytes that underwent apoptosis. Reverse-genetic replacement of the GP in strain ARM with WE-GP resulted in only a very modest increase in liver pathogenicity, if any. Yet, an ARM-derived variant virus with a mutated polymerase gene caused severe liver disease when engineered to display WE-GP but considerably less when expressing ARM-GP. This reverse-genetic approach to an animal model of arenaviral hepatitis reveals a previously underestimated contributory role of the GP that alone is, however, insufficient to cause disease.
authors.affiliation: Institute of Experimental Immunology, Department of Pathology, University Hospital of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergthaler
authors.affiliation: Department of Neuropathology, Georg August University, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
authors.forename: Doron
authors.initials: D
authors.lastname: Merkler
authors.affiliation: Institute of Experimental Immunology, Department of Pathology, University Hospital of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
authors.forename: Edit
authors.initials: E
authors.lastname: Horvath
authors.affiliation: Institute of Clinical Chemistry, University Hospital of Zurich, Ramistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Bestmann
authors.affiliation: Institute of Experimental Immunology, Department of Pathology, University Hospital of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Pinschewer
mesh_terms: D000818:Animals; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000473:pathology / Q000821:virology; D007728:Kupffer Cells / Q000473:pathology / Q000821:virology; D008107:Liver Diseases / Q000473:pathology* / Q000821:virology; D008216:Lymphocytic Choriomeningitis / Q000473:pathology* / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000472:pathogenicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence
chemical_list: D006023:Glycoproteins; D014759:Viral Envelope Proteins; D012194:RNA-Directed DNA Polymerase