Mouse models: intrahepatic immunology and viral hepatitis

Mouse models: intrahepatic immunology and viral hepatitis

Human hepatitis viruses are very picky. Not only do they prefer differentiated hepatocytes as their exclusive target cells, they also have a very narrow host range, infecting only higher primates. Studying their replication in vitro therefore requires cell lines transduced with human host factors or cell lines skewed in their innate immune defense. Obviously, this hampers insight in how these viruses circumvent primary innate immune responses. But also, these adaptations make the study of adaptive immune responses difficult.

In our endeavor to unravel innate cellular immune responses against human hepatitis viruses, we apply two different mouse models:

1) Mice with chimeric livers reconstituted by human hepatocytes. In these animals genuine hepatitis B, C and E viruses are inoculated. These animals are immune deficient to prevent rejection of the human hepatocyte graft.
2) The natural mouse pathogen lymphocytic choriomeningitis virus(LCMV) induces, apart from a systemic viral infection, chronic liver inflammation that is cleared after a variable period of several weeks.

Our research sets out to make use of both mouse models to study fundamental aspects of viral replication and the interaction of the innate immune system with HBV, HCV, HEV or LCMV as a surrogate virus. The ultimate goal is to identify critical viral or immune components, which tip the balance towards chronicity instead of self-resolving acute infection.

figure mouse model


 

For more information, please contact Thomas Vanwolleghem (t.vanwolleghem @erasmusmc.nl).


Collaborations
These studie are performed in close collaboration with the dept of Viroscience at the Erasmus (dr. Pas, dr. Haagmans), as well as numerous national (dr. Zaaijer, AMC) and international collaborators (UZA Antwerp; CODA-CERVA, Brussels; dr. Thiry, Liege; dr. Zuniga, UCLA San Diego; dr. Gama, John Hopkins). 


References

  • van de Garde MD, Pas SD, van der Net G, de Man RA, Osterhaus AD, Haagmans BL, Boonstra A, Vanwolleghem T.
    Hepatitis E Virus (HEV) Genotype 3 Infection of Human Liver Chimeric Mice as a Model for Chronic HEV Infection.
    J Virol. 2016 Apr 14;90(9):4394-401.
  • Movita D, van de Garde MD, Biesta P, Kreefft K, Haagmans B, Zuniga E, Herschke F, De Jonghe S, Janssen HL, Gama L, Boonstra A, Vanwolleghem T.
    Inflammatory monocytes recruited to the liver within 24 hours after virus-induced inflammation resemble Kupffer cells but are functionally distinct.
    J Virol. 2015 May;89(9):4809-17.
  • Vanwolleghem T, Libbrecht L, Hansen BE, Desombere I, Roskams T, Meuleman P, Leroux-Roels G.
    Factors determining successful engraftment of hepatocytes and susceptibility to hepatitis B and C virus infection in uPA-SCID mice. 
    J Hepatol. 2010. 53:468- 476.
  • Boonstra A, van der Laan LJW, Vanwolleghem T, Janssen HLA.
    Experimental models for hepatitis C viral infection.
    Hepatology. 2009. 50: 1646-1655.
  • Movita D, Kreefft K, Biesta P, van Oudenaren A, Leenen PJ, Janssen HL, Boonstra A
    Kupffer cells express a unique combination of phenotypic and functional characteristics compared with splenic and peritoneal macrophages. 
    J Leukoc Biol 2012. 92 (4): 723-733.