Skip to main content

Advertisement

Log in

Development of murine models to study Hepatitis C virus induced liver pathogenesis

  • Review Article
  • Published:
Indian Journal of Virology Aims and scope Submit manuscript

Abstract

Hepatitis C virus (HCV) is involved in different liver pathologies worldwide. In contemporary scenario, HCV treatment is lagging behind owing to absence of vaccines against virus. The only consideration for HCV treatment is pegylated interferon-alpha and ribavirin that results in sustained virological response in 50 % of patients. Two feasible hosts for HCV infection are chimpanzee and humans. For decades, chimpanzees are sole host to study HCV pathogenesis, but their use is limited due to ethical issues. The dilemma behind HCV therapy is the need of sustainable animal models that can help simulate in vivo conditions. We have assembled recent advances in animal models to study liver diseases for targeted therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Awatramani R, Soriano P, Mai JJ, Dymecki S. An Flp indicator mouse expressing alkaline phosphatase from the ROSA26 locus. Nat Genet. 2001;29:257–259.

    Article  PubMed  CAS  Google Scholar 

  2. Bissig KD, Wieland SF, Tran P, Isogawa M, Le TT, Chisari FV, Verma IM. Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J Clin Invest. 2010;120:924–930.

    Article  PubMed  CAS  Google Scholar 

  3. Brunner AM, Lioubin MN, Marquardt H, Malacko AR, Wang WC, Shapiro RA, Neubauer M, Cook J, Madisen L, Purchio AF. Site-directed mutagenesis of glycosylation sites in the transforming growth factor-beta 1 (TGF beta 1) and TGF beta 2 precursors and of cysteine residues within mature TGF beta 1: effects on secretion and bioactivity. Mol Endocrinol. 1992;6:1691–1700.

    Article  PubMed  CAS  Google Scholar 

  4. Calvisi DF, Conner EA, Ladu S, Lemmer ER, Factor VM,Thorgeirsson SS. Activation of the canonical Wnt/beta-catenin pathway confers growth advantages in c-Myc/E2F1 transgenic mouse model of liver cancer. J Hepatol. 2005;42:842–849.

    Article  PubMed  CAS  Google Scholar 

  5. Capecchi MR. Altering the genome by homologous recombination. Science. 1989;244:1288–1292.

    Article  PubMed  CAS  Google Scholar 

  6. Conner EA, Lemmer ER, Omori M, Wirth PJ, Factor VM, Thorgeirsson SS. Dual functions of E2F-1 in a transgenic mouse model of liver carcinogenesis. Oncogene. 2000;19:5054–5062.

    Article  PubMed  CAS  Google Scholar 

  7. Dorner M, Horwitz JA, Robbins JB, Barry WT, Feng Q, Mu K, Jones CT, Schoggins JW, Catanese MT, Burton DR, Law M, Rice CM, Ploss A. A genetically humanized mouse model for Hepatitis C virus infection. Nature. 2011;474:208–211.

    Article  PubMed  CAS  Google Scholar 

  8. Hahn E, Wick G, Pencev D, Timpl R. Distribution of basement membrane proteins in normal and fibrotic human liver: collagen type IV, laminin, and fibronectin. Gut. 1980;21:63–71.

    Article  PubMed  CAS  Google Scholar 

  9. Harbour JW, Dean DC. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 2000;14(19):2393–2409.

    Article  PubMed  CAS  Google Scholar 

  10. Hazari S, Hefler HJ, Chandra PK, Poat B, Gunduz F, Ooms T, Wu T, Balart LA, Dash S. Hepatocellular carcinoma xenograft supports HCV replication: a mouse model for evaluating antivirals. World J Gastroenterol. 2011;17:300.

    Article  PubMed  Google Scholar 

  11. Ilan E, Arazi J, Nussbaum O, Zauberman A, Eren R, Lubin I, Neville L, Ben-Moshe O, Kischitzky A, Litchi A, Margalit I, Gopher J, Mounir S, Cai W, Daudi N, Eid A, Jurim O, Czerniak A, Galun E, Dagan S. The Hepatitis C virus (HCV)-trimera mouse: a model for evaluation of agents against HCV. J Infect Dis. 2002;185:153–161.

    Article  PubMed  CAS  Google Scholar 

  12. Jaenisch R. Transgenic animals. Science. 1988;240:1468–1474.

    Article  PubMed  CAS  Google Scholar 

  13. Kanzler S, Lohse AW, Keil A, Henninger J, Dienes HP, Schirmacher P, Rose-John S, zum Buschenfelde KH, Blessing M. TGF-beta1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis. Am J Physiol. 1999;276:G1059–1068.

    PubMed  CAS  Google Scholar 

  14. Kneteman NM, Weiner AJ, O’Connell J, Collett M, Gao T, Aukerman L, Kovelsky R, Ni ZJ, Zhu Q, Hashash A, Kline J, Hsi B, Schiller D, Douglas D, Tyrrell DL, Mercer DF. Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application. Hepatology 2006;43:1346–1353.

    Article  PubMed  CAS  Google Scholar 

  15. Knittel T, Janneck T, Muller L, Fellmer P, Ramadori G. Transforming growth factor beta 1-regulated gene expression of Ito cells. Hepatology. 1996;2:352–360.

    Article  Google Scholar 

  16. Kremsdorf D, Brezillon N. New animal models for Hepatitis C viral infection and pathogenesis studies. World J Gastroenterol. 2007;13:2427–2435.

    Google Scholar 

  17. Legrand N, Ploss A, Balling R, Becker PD, Borsotti C, Brezillon N, Debarry J, de Jong Y, Deng H, Di Santo JP, Eisenbarth S, Eynon E, Flavell RA, Guzman CA, Huntington ND, Kremsdorf D, Manns MP, Manz MG, Mention JJ, Ott M, Rathinam C, Rice CM, Rongvaux A, Stevens S, Spits H, Strick-Marchand H, Takizawa H, van Lent AU, Wang C, Weijer K, Willinger T, Ziegler P. Humanized mice for modeling human infectious disease: challenges, progress, and outlook. Cell Host Microbe. 2009;6:5–9.

    Article  PubMed  CAS  Google Scholar 

  18. Legrand N, Weijer K, Spits H. Experimental models to study development and function of the human immune system in vivo. J Immunol. 2006;176(4):2053–2058.

    PubMed  CAS  Google Scholar 

  19. Mansour SL, Thomas KR, Capecchi MR. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes. Nature. 1988; 336(6197):348–352.

    Article  PubMed  CAS  Google Scholar 

  20. Manz MG. Human-hemato-lymphoid-system mice: opportunities and challenges. Immunity. 2007;26:537–541.

    Article  PubMed  CAS  Google Scholar 

  21. The transforming growth factor-beta family. Annu Rev Cell Biol. 1990;6:597–641.

    Article  PubMed  CAS  Google Scholar 

  22. Mercer DF, Schiller DE, Elliott JF, Douglas DN, Hao C, Rinfret A, Addison WR, Fischer KP, Churchill TA, Lakey JR, Tyrrell DL, Kneteman NM. Hepatitis C virus replication in mice with chimeric human livers. Nat Med. 2001;7:927–933.

    Article  PubMed  CAS  Google Scholar 

  23. Meuleman P, Leroux-Roels G. The human liver-uPA–SCID mouse: a model for the evaluation of antiviral compounds against HBV and HCV. Antiviral Res. 2008;80:231–238.

    Article  PubMed  CAS  Google Scholar 

  24. Murakami H, Sanderson ND, Nagy P, Marino PA, Merlino G, Thorgeirsson SS. Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c-myc and transforming growth factor alpha in hepatic oncogenesis. Cancer Res. 1993;53:1719–1723.

    PubMed  CAS  Google Scholar 

  25. Pawlotsky JM, Chevaliez S, McHutchison JG. The Hepatitis C virus life cycle as a target for new antiviral therapies. Gastroenterology 2007;132:1979–1998.

    Article  PubMed  CAS  Google Scholar 

  26. Ploss A, Rice CM. Towards a small animal model for Hepatitis C. EMBO Rep. 2009;10:1220–1227.

    Article  PubMed  CAS  Google Scholar 

  27. Porter FD, Drago J, Xu Y, Cheema SS, Wassif C, Huang SP, Lee E, Grinberg A, Massalas JS, Bodine D. Lhx2, a LIM homeobox gene, is required for eye, forebrain, and definitive erythrocyte development. Development. 1997;124:2935–2944.

    PubMed  CAS  Google Scholar 

  28. Radbill BD, Gupta R, Ramirez MC, DiFeo A, Martignetti JA, Alvarez CE, Friedman SL, Narla G, Vrabie R, Bowles R, Saiman Y, Bansal MB. Loss of matrix metalloproteinase-2 amplifies murine toxin-induced liver fibrosis by upregulating collagen I expression. Dig Dis Sci. 2011;56:406–416.

    Article  PubMed  CAS  Google Scholar 

  29. Ralston R, Thudium K, Berger K, Kuo C, Gervase B, Hall J, Selby M, Kuo G, Houghton M, Choo QL. Characterization of Hepatitis C virus envelope glycoprotein complexes expressed by recombinant vaccinia viruses. J Virol. 1993;67:6753–6761.

    PubMed  CAS  Google Scholar 

  30. Rhim JA, Sandgren EP, Palmiter RD, Brinster RL. Complete reconstitution of mouse liver with xenogeneic hepatocytes. Proc Natl Acad Sci USA. 1995;92:4942–4946.

    Article  PubMed  CAS  Google Scholar 

  31. Rosenbaum J, Blazejewski S. Regulation of Ito cell proliferation by soluble factors. J Hepatol. 1995;22:65–70.

    Article  PubMed  CAS  Google Scholar 

  32. Santoni-Rugiu E, Nagy P, Jensen MR, Factor VM, Thorgeirsson SS. Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-alpha. Am J Pathol. 1996;149:407–428.

    PubMed  CAS  Google Scholar 

  33. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011;472:481–485.

    Article  PubMed  CAS  Google Scholar 

  34. Shibata S, Asano T, Ogura A, Hashimoto N, Hayakawa J, Uetsuka K, Nakayama H, Doi K. SCID-bg mice as xenograft recipients. Lab Anim. 1997;31:163–168.

    Article  PubMed  CAS  Google Scholar 

  35. Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol. 2007;7(2):118–130.

    Article  PubMed  CAS  Google Scholar 

  36. Turrini P, Sasso R, Germoni S, Marcucci I, Celluci A, Di Marco A, Marra E, Paonessa G, Eutropi A, Laufer R, Migliaccio G,Padron J. Development of humanized mice for the study of Hepatitis C virus infection. Transplant Proc. 2006;38:1181–1184.

    Article  PubMed  CAS  Google Scholar 

  37. Wandzioch E, Kolterud A, Jacobsson M, Friedman SL, Carlsson L.nLhx2 −/− mice develop liver fibrosis. Proc Natl Acad Sci USA. 2004;101:16549–16554.

    Article  PubMed  CAS  Google Scholar 

  38. Washburn ML, Bility MT, Zhang L, Kovalev GI, Buntzman A, Frelinger JA, Barry W, Ploss A, Rice CM, Su L. A humanized mouse model to study Hepatitis C virus infection, immune response, and liver disease. Gastroenterology. 2011;140:1334–1344.

    Article  PubMed  CAS  Google Scholar 

  39. Webster DP, Klenerman P, Collier J, Jeffery KJ. Development of novel treatments for Hepatitis C. Lancet Infect Dis. 2009;9:108–117.

    Article  PubMed  CAS  Google Scholar 

  40. Wu GY, Konishi M, Walton CM, Olive D, Hayashi K, Wu CH. A novel immunocompetent rat model of HCV infection and hepatitis. Gastroenterology. 2005;128:1416–1423.

    Article  PubMed  CAS  Google Scholar 

  41. Zeuzem S, Berg T, Moeller B, Hinrichsen H, Mauss S, Wedemeyer H, Sarrazin C, Hueppe D, Zehnter E, Manns MP. Expert opinion on the treatment of patients with chronic Hepatitis C. J Viral Hepat. 2009;16(2):75–90.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Financial support by National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan to conduct this research is highly acknowledged.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sobia Manzoor.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Khalid, M., Manzoor, S., Imran, M. et al. Development of murine models to study Hepatitis C virus induced liver pathogenesis. Indian J. Virol. 24, 151–156 (2013). https://doi.org/10.1007/s13337-013-0152-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13337-013-0152-1

Keywords

Navigation