Our laboratory is focused on understanding the immune system of the liver during virus infection and fatty liver disease. Inflammatory liver diseases such as chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) are leading causes for the development of liver cirrhosis and hepatocellular carcinoma (HCC).

As a major metabolic organ of the body the liver is prone towards immune tolerance as it is constantly exposed to gut-derived blood rich in bacterial and dietary antigens. The liver is also enriched in various tissue-resident innate, innate-like and adaptive immune cell populations, such as Kupffer cells, natural killer (NK) cells, invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and CD4+ and CD8+ T cell subsets. This unique immunological microenvironment may play an essential role in controlling the outcome of a hepatic virus infection as well as the development of immunopathology and liver disease progression during inflammatory liver disease. It is our aim to understand how different immune cells subsets and their interactions in this tissue-specific environment contribute to the opposing outcomes of: 1) viral clearance and protection from secondary infection versus establishment of a chronic viral infection and 2) tissue protection and repair versus development of immunopathology and progressive liver disease. 

However, studying these mechanisms is notoriously difficult. Access to human liver tissue, in particular during acute viral infection, is extremely limited. Clinically relevant human hepatitis viruses A-E have a narrow host tropism to the human liver and immune-competent small animal models do not exist. Given these limitations we have a longstanding interest in the development of immune-competent mouse models for the study of hepatotropic virus infections and liver disease. Interestingly, in recent years various hepatitis C virus (HCV)-related animal viruses were discovered in horses, bats or rodents, which opened the door for the development of HCV surrogate models. In 2014, an HCV-related rodent hepacivirus, named Norway rat hepacivirus (NrHV) was discovered in wild rats of New York City (Firth et al. mBio 2014). Subsequently, we showed that NrHV can establish a hepatotropic infection in common immune-competent laboratory mouse strains. We could also show that NrHV infection in mice shares several virological and immunological key features with HCV infection in humans (Billerbeck et al. Science 2017). 

Using the NrHV mouse model and mouse models of diet-induced fatty liver disease we aim to gain new insight into protective and detrimental hepatic immune mechanisms during inflammatory liver disease. We are further interested in the development of mouse models that reliably recapitulate human end-stage liver disease, such as cirrhosis and HCC. Our long-term goal is to translate basic findings from mouse models to the human liver and to develop new strategies for HCV vaccine design or immune-therapeutic treatment options for liver disease. 

Raus S, Lopez-Scarim J, Luthy J and Billerbeck E. Hepatic iNKT cells produce type 2 cytokines and restrain antiviral T cells during acute hepacivirus infection. Front Immunol. 2022 Sept 8; 13:953151. doi: 10.3389/fimmu.2022.953151

Wu X, Dao Thi VL, Huang Y, Billerbeck E, Saha D, Hoffmann HH, Wang Y, Silva LAV, Sarbanes S, Sun T, Andrus L, Yu Y, Quirk C, Li M, MacDonald MR, Schneider WM, An X, Rosenberg BR, Rice CM. Intrinsic immunity shapes viral resistance of stem cells. Cell. 2018 Jan 25;172(3):423-438.e25. doi: 10.1016/j.cell.2017.11.018. 

Trivedi S, Murthy S, Sharma H, Hartlage AS, Kumar A, Gadi S, Simmonds P, Chauhan LV, Scheel TKH, Billerbeck E, Burbelo PD, Rice CM, Lipkin WI, Vandergrift K, Cullen JM, Kapoor A. Viral persistence, liver disease and host response in Hepatitis C-like virus rat model. Hepatology. 2018 Aug;68(2):435-448. doi: 10.1002/hep.29494. 

Billerbeck E, Wolfisberg R, Fahnoe U, Xiao WJ, Quirk C, Luna JM, Cullen JM, Hartlage AS, Chiriboga C, Ghoshal K, Lipkin IW, Bukh J, Scheel TKH, Kapoor A, Rice CM. Mouse models of acute and chronic hepacivirus infection. Science. 2017 Jul 14;357(6347):204-208. 

Billerbeck E*, Mommersteeg MC*, Shlomai A, Xiao JW, Andrus L, Bhatta A, Vercauteren K, Michaillidis E, Dorner M, Krishnan A, Charlton MR, Chiriboga L, Rice CM, de Jong YP. Humanized mice efficiently engrafted with fetal hepatoblasts and syngeneic immune cells develop human monocytes and NK cells. J Hepatol. 2016 Aug;65(2):334-43. 

* equal contribution 

Billerbeck E, Barry WT, Mu K, Dorner M, Rice CM, Ploss A. Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor-, granulocyte-macrophage colony-stimulation factor-, interleukin3-expressing NOD-SCID IL2Ry(null) humanized mice. Blood. 2011 Mar 17;117(11):3076-86

Billerbeck E*, Kang YH*, Walker L, Lockstone H, Grafmueller S, Fleming V, Flint J, Willberg CB, Bengsch B, Seigel B, Ramamurthy N, Zitzmann N, Barnes EJ, Thevanayagam J, Bhagwanani A, Leslie A, Oo YH, Kollnberger S, Bowness P, Drognitz O, Adams DH, Blum HE, Thimme R, Klenerman P. Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3006-11

 * equal contribution