Contributions of the lymphocytic choriomeningitis virus glycoprotein and polymerase to strain-specific differences in murine liver pathogenicity.
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.
Bergthaler
Andreas
A
Institute of Experimental Immunology, Department of Pathology, University Hospital of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
Merkler
Doron
D
Department of Neuropathology, Georg August University, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
Horvath
Edit
E
Institute of Experimental Immunology, Department of Pathology, University Hospital of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
Bestmann
Lukas
L
Institute of Clinical Chemistry, University Hospital of Zurich, Ramistrasse 100, 8091 Zurich, Switzerland.
Pinschewer
Daniel D
DD
Institute of Experimental Immunology, Department of Pathology, University Hospital of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
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
D006023:Glycoproteins; D014759:Viral Envelope Proteins; D012194:RNA-Directed DNA Polymerase