Viral infections of the liver

Viral infections of the liver by hepatitis viruses, e.g. hepatitis B virus (HBV) or hepatitis C virus (HCV), lead to acute hepatitis, which can further develop into chronic hepatitis. Chronic viral hepatitis is a potentially life-threatening disease that affects currently more than 350 million people. The decision of whether an infection leads to an acute self-limited disease or develops into a chronic infection is not entirely understood.

In recent years, my lab strived for a better understanding of how antiviral immunity is regulated in the liver and unraveled new concepts of antiviral immune effector function. To this end, we not only aim to understand the local regulation and dynamics of CD8 T cells but also the role of virus-infected target cells. CD8 T cells are key to eliminating virus-infected hepatocytes leading to liver disease but also to elimination or control of the viral infection. One determinant of CD8 T cell function is the antigen levels. Previously, we have shown that low antigen levels, presented by infected hepatocytes, lead to chronic viral infection of the liver (Manske et al. 2008). In contrast, high numbers of virus-infected hepatocytes, associated with high antigen levels, may also lead to chronic HBV infection because of CD8 T cell dysfunction (Manske, Schneider, et al., 2021). This indicates a delicate balance between antigen levels, the number of infected hepatocytes, and the outcome of antiviral immunity. In order to investigate immunity against HBV in the liver, we have developed adenoviral vectors delivering replication-competent HBV genomes to the liver in combination with highly sensitive luciferase expression that allows for the detection of antiviral immunity and antigen levels in real-time. Using this model system, in combination with single-cell RNA sequencing (scRNAseq) we recently identified a liver resident Tcf1+ CD8 T cell progenitor population. These progenitor cells can be stimulated during chronic viral infection to reconstitute antiviral immunity leading to clearance of HBV infection. In the future, we aim to further identify mechanisms that regulate the local effector function of virus-specific T cells and manipulate those toward a cure of chronic infections. 

Besides CD8 T cell function, the efficacy of antiviral immunity can also be regulated on the level of the infected target cells. We have recently demonstrated that viral infection changes mitochondrial stress resilience enabling apoptosis execution upon TNF stimulation (Schneider, Kurz, et al. 2021 and Lampl et al, 2020). This reduced stress resilience sets the basis for the non-canonical cytotoxic T lymphocyte effector function in the liver, which accounts for at least 50% of total antiviral immunity (Wohlleber et al., 2012). The reasons for the reduced mitochondrial stress resilience are linked to strong viral gene expression, however, lacking further and deeper knowledge and will be investigated in the future.

PD Dr. Dirk Wohlleber
Research Group Leader
Institut für Molekulare Immunologie
Ismaninger Straße 22
81675 München
Team members

Manske K, Schneider A, Ko C, Knolle PA, Steiger K, Protzer U, Wohlleber D. In Vivo Bioluminescence Imaging of HBV Replicating Hepatocytes Allows for the Monitoring of Anti-Viral Immunity. Viruses. 2021 Nov 13;13(11):2273.  

Lampl S, Janas MK, Donakonda S, Brugger M, Lohr K, Schneider A, Manske K, Sperl LE, Kläger S, Küster B, Wettmarshausen J, Müller C, Laschinger M, Hartmann D, Hüser N, Perocchi F, Schmitt-Kopplin P, Hagn F, Zender L, Hornung V, Borner C, Pichlmair A, Kashkar H, Klingenspor M, Prinz M, Schreiner S, Conrad M, Jost PJ, Zischka H, Steiger K, Krönke M, Zehn D, Protzer U, Heikenwälder M, Knolle PA*, Wohlleber D*. Reduced mitochondrial resilience enables non-canonical induction of apoptosis after TNF receptor signaling in virus-infected hepatocytes. J Hepatol. 2020 Dec;73(6):1347-1359.  

Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, Utzschneider DT, von Hoesslin M, Cullen JG, Fan Y, Eisenberg V, Wohlleber D, Steiger K, Merkler D, Delorenzi M, Knolle PA, Cohen CJ, Thimme R, Youngblood B, Zehn D.TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature. 2019 Jul;571(7764):265-269.  

Schneider A, Kurz S, Manske K, Janas M, Heikenwälder M, Misgeld T, Aichler M, Weissmann SF, Zischka H, Knolle P, Wohlleber D. Single organelle analysis to characterize mitochondrial function and crosstalk during viral infection. Sci Rep. 2019 Jun 11;9(1):8492.

Welz M, Eickhoff S, Abdullah Z, Trebicka J, Gartlan KH, Spicer JA, Demetris AJ, Akhlaghi H, Anton M, Manske K, Zehn D, Nieswandt B, Kurts C, Trapani JA, Knolle P*, Wohlleber D*, Kastenmüller W*. Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis. Nat Commun. 2018 Nov 15;9(1):4805.  

Manske K, Kallin N, König V, Schneider A, Kurz S, Bosch M, Welz M, Cheng RL, Bengsch B, Steiger K, Protzer U, Thimme R, Knolle PA, Wohlleber D. Outcome of Antiviral Immunity in the Liver Is Shaped by the Level of Antigen Expressed in Infected Hepatocytes. Hepatology. 2018 Dec;68(6):2089-2105.  

Wohlleber D, Kashkar H, Gärtner K, Frings MK, Odenthal M, Hegenbarth S, Börner C, Arnold B, Hämmerling G, Nieswandt B, van Rooijen N, Limmer A, Cederbrant K, Heikenwalder M, Pasparakis M, Protzer U, Dienes HP, Kurts C, Krönke M, Knolle PA. TNF-induced target cell killing by CTL activated through cross-presentation. Cell Rep. 2012 Sep 27;2(3):478-87. 

The current list of our publications can be found on Pubmed.


We are currently funded by:

SFB TRR179: Dynamics of antiviral immunity against hepatitis B virus in the liver. 

DFG: Die zentrale Rolle von Virus-infizierten Hepatozyten in der Modulation der antiviralen Immunantwort in der Leber