AG Heikenwälder

Mathias Heikenwälder
 

Phone: +49 (0)6221-56 4225

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Research Team Members

Research Projects

I. On the role of platelets in affecting Hepatitis B virus replication and clearance by modulating the liver tissue environment

Hepatitis B virus (HBV) chronically infects around 250 million people worldwide (WHO data, 2016) and increases the risk of developing liver cirrhosis and hepatocellular carcinoma. HBV has evolved several mechanisms to shape the hepatic inflammatory signature as well as polarize innate and adaptive immune cells in the liver microenvironment to be able to persistently infect the liver, thus causing chronic liver damage (Haybaeck et al., Cancer Cell 2009; Ringelhan et al., Nature Immunology. 2018). Recently, we have identified a key role of platelets in shaping the liver microenvironment in murine and human liver tissue specimen by applying preclinical mouse models and performing a clinical trial, respectively (Mahlemir et al., Nature Medicine 2019). Our data indicate that platelets control the influx of CD8+ T-cells into the liver by binding with their CD44 surface molecule to hepatocyte- and Kupffer cell-derived hyaluronic acid and attract/retain several adaptive and innate immune cells by secreting inflammatory cargo. Notably, we could selectively dissect the inflammatory role of platelets from their role in hemostasis and bleeding. Our data indicate that platelets, beside their function in hemostasis, can directly cross-talk with hepatocytes, adaptive and innate immune cells, altering their metabolic, inflammatory and proliferative functions and contributing to the polarization and activity of immune cells.

In the future, we aim to examine the effect of platelet activation, platelet-derived molecules and platelet-triggered cross-talk with hepatocytes and immune cells in the context of HBV-induced hepatitis and HBV replication. We will focus on the identification of pathways that are directly activated or suppressed by platelets within (1) hepatocytes to affect virus replication and (2) within immune cells to alter polarization, immune status and anti-HBV responses. Using different knock-out mouse strains or therapeutic regimen affecting platelet biology we will apply models of chronic and acute HBV infection (e.g. AAV-based) as well as other models of chronic virus infection (e.g. LCMV) to test the role of platelets in contributing to infection-related changes of the liver tissue microenvironment and to shaping anti-HBV responses. Moreover, we will use a newly established liver 3D-culture model (termed liveroid), which allows long term HBV-infection of genuine human liver tissue for more than 4 weeks, to test the direct/indirect role of platelets on hepatocytes and on immune cells controlling HBV replication.

II. ROLE OF T-CELL DERIVED LYMPHOTOXIN IN CONTRIBUTING TO THE LIVER MICROENVIRONMENT IN VIRAL HEPATITIS

Liver-directed immune responses are a general key objective of our group. In the past we have identified that Lymphotoxin (LT; LTab) expressed by T cells plays a major role in shaping the liver microenvironment (Haybaeck et al., Cancer Cell 2010; Finkin et al., Nature Immunology 2015). We have generated tools or use tools with which we can abrogate or overexpress LT expression on T-cells specifically (e.g. T-cell specific transgenic overexpression: lck-LTab tg mice; CD4-Cre LTa loxP/loxP). We have tested in the context of T cell migration, hepatic viral infection (e.g, LCMV) as well as antigen presentation (in vivo and in vitro), how LT expression affects T-cell migration into the liver, T-cell survival, viral clearance and antigen recognition (Heikenwalder et al., American Journal of Pathology 2008). Our data indicate that increased LT expression on T cells increases the efficacy of T cell homing into the liver, T cell persistence in the liver as well as killing of target cells. Thus, modulation of LT expression on T cells greatly affects the efficacy of T cell dynamics, survival and killing of viral infected cells. We have demonstrated that T-cell derived LT induces NF-kb signaling in hepatocytes that affects HBV clearance (Lucifora et al., Science 2014). By looking at HBV replication in vitro and LCMV-replication in vivo we demonstrated that hepatocyte-derived NF-kb signaling in hepatocyte indeed plays a dual role in attracting virus-specific CD8+ T cells and in amplifying IFN responses (Namineni et al., J Hepatol 2019) - thereby controlling viral clearance efficacy. In the future, we will dissect the underlying molecular mechanisms.