Characterization of liver histopathology in a transgenic mouse model expressing genotype 1a hepatitis C virus core and envelope proteins 1 and 2.
Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatocellular carcinoma worldwide. The purpose of this study was to determine how the HCV structural proteins affect the dynamic structural and functional properties of hepatocytes and measure the extra-hepatic manifestations induced by these viral proteins. A transgenic mouse model was established by expressing core, E1 and E2 proteins downstream of a CMV promoter. HCV RNA was detected using RT-PCR in transgenic mouse model tissues, such as liver, kidney, spleen and heart. Expression of the transgene was analysed by real-time PCR to quantify viral RNA in different tissues at different ages. Immunofluorescence analysis revealed the expression of core, E1 and E2 proteins predominantly in hepatocytes. Lower levels of protein expression were detected in spleen and kidneys. HCV RNA and viral protein expression increased in the liver with age. Histological analysis of liver cells demonstrated steatosis in transgenic mice older than 3 months, which was more progressed with age. Electron microscopy analysis revealed alterations in nuclei, mitochondria and endoplasmic reticulum. HCV structural proteins induce a severe hepatopathy in the transgenic mouse model. These mice became more prone to liver and lymphoid tumour development and hepatocellular carcinoma. In this model, the extra-hepatic effects of HCV, which included swelling of renal tubular cells, were mild. It is likely that the HCV structural proteins mediate some of the histological alterations in hepatocytes by interfering with lipid transport and liver metabolism.
Naas
Turaya
T
Department of Microbiology Immunology and Biochemistry, University of Ottawa, Ottawa, ON, Canada, K1N 6N5.|Division of Virology, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada, K1H 8L1.
Ghorbani
Masoud
M
Division of Virology, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada, K1H 8L1.
Alvarez-Maya
Ikuri
I
Division of Virology, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada, K1H 8L1.
Lapner
Michael
M
Division of Virology, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada, K1H 8L1.
Kothary
Rashmi
R
Ottawa Health Research Institute, Molecular Medicine Program, Ottawa, ON, Canada, K1H 8L6.
De Repentigny
Yves
Y
Ottawa Health Research Institute, Molecular Medicine Program, Ottawa, ON, Canada, K1H 8L6.
Gomes
Susantha
S
Department of Veterinary Pathology, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, SK, Canada, S7N 5B4.
Babiuk
Lorne
L
Department of Veterinary Microbiology, Veterinary Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK, Canada, S7N 5E3.
Giulivi
Antonio
A
Division of Blood Borne Pathogens, Health Canada, Ottawa, ON, Canada, K1A 0L2.
Soare
Catalina
C
Department of Microbiology Immunology and Biochemistry, University of Ottawa, Ottawa, ON, Canada, K1N 6N5.|Division of Virology, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada, K1H 8L1.
Azizi
Ali
A
Department of Microbiology Immunology and Biochemistry, University of Ottawa, Ottawa, ON, Canada, K1N 6N5.|Division of Virology, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada, K1H 8L1.
Diaz-Mitoma
Francisco
F
Department of Microbiology Immunology and Biochemistry, University of Ottawa, Ottawa, ON, Canada, K1N 6N5.|Division of Virology, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, Canada, K1H 8L1.
D000367:Age Factors; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology; D002467:Cell Nucleus / Q000473:pathology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000473:pathology / Q000821:virology; D005234:Fatty Liver / Q000473:pathology / Q000821:virology; D005260:Female; D019337:Hematologic Neoplasms / Q000473:pathology / Q000821:virology; D006526:Hepatitis C / Q000473:pathology* / Q000821:virology*; D022781:Hepatocytes / Q000473:pathology; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology*; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology; D014758:Viral Core Proteins / Q000235:genetics; D014759:Viral Envelope Proteins / Q000235:genetics
C087035:E1 protein, Hepatitis C virus; D014758:Viral Core Proteins; D014759:Viral Envelope Proteins; C069130:nucleocapsid protein, Hepatitis C virus; C091015:glycoprotein E2, Hepatitis C virus