title: Hepatitis C Virus Nonstructural 3/4A Protein Dampens Inflammation and Contributes to Slow Fibrosis Progression during Chronic Fibrosis In Vivo.
abstract: HCV infection typically induces liver injury and inflammation, which appears to be responsible for the associated fibrogenesis. To date, the mechanism underlying the different rates of disease progression remains unclear. The aim of the study is to understand the possible role of the HCV non-structural (NS) 3/4A protein in the fibrosis progression. We used NS3/4A-expressing transgenic mice (NS3/4A-Tg) to accomplish the goals of the study. Different stages of liver fibrosis were induced in wild-type and NS3/4A-Tg mice by single carbon tetrachloride (acute) or multiple injections for 4 (intermediate) or 8 (chronic) weeks. Fibrotic parameters, inflammatory responses and hepatocyte turnover were extensively examined. Hepatic expression of HCV NS3/4A did not induce spontaneous liver damage. However, NS3/4A expression exerted contrasting effects during acute and chronic liver damage. During early fibrogenesis and intermediate fibrosis (4 weeks), NS3/4A-Tg mice exhibited enhanced liver damage whereas reduced fibrosis was observed in NS3/4A-Tg during chronic liver fibrosis (8 weeks). Furthermore, attenuated inflammation was observed in NS3/4A-Tg during chronic fibrosis with increase in M2 macrophages, hepatocyte proliferation, decreased hepatocyte apoptosis and decreased ductular reaction. In conclusion, during early fibrogenesis, HCV NS3/4A contributes to liver damage. While, during chronic liver fibrosis, NS3/4A dampens inflammation and induces hepatocyte regeneration thereby contributing to slow fibrosis progression to promote its survival or persistence.
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden; Targeted Therapeutics, Department of Biomaterials, Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Bansal
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Frelin
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Erwin Daniel
authors.initials: ED
authors.lastname: Brenndörfer
authors.affiliation: Targeted Therapeutics, Department of Biomaterials, Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.affiliation: Targeted Therapeutics, Department of Biomaterials, Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
authors.forename: Jai
authors.initials: J
authors.lastname: Prakash
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Matti
authors.initials: M
authors.lastname: Sällberg
mesh_terms: D000208:Acute Disease; D000818:Animals; D002251:Carbon Tetrachloride; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D002908:Chronic Disease; D018450:Disease Progression; D015870:Gene Expression; D016174:Hepacivirus / Q000235:genetics* / Q000254:growth & development; D019698:Hepatitis C, Chronic / Q000473:pathology / Q000821:virology*; D022781:Hepatocytes / Q000473:pathology / Q000821:virology*; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000473:pathology / Q000821:virology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000473:pathology / Q000821:virology*; D008264:Macrophages / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D019076:Transgenes; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D002251:Carbon Tetrachloride; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus