Head of the Department
Phone: +49 (0)6221-56 4225
Fax: +49 (0)6221-56 4570
Our original interests focused on the molecular virology of HCV, including the development of robust cell culture models and their use to study the viral replication cycle. In the last few years, we put an emphasis on virus – host cell interaction by using novel imaging methods and high resolution microscopy. Moreover, we are actively working on innate immune responses induced by infections and viral countermeasures. Finally, we integrated systems biology approaches in combination with mathematical modeling of biological processes. By including the Dengue virus into our research portfolio, we are able to compare how a persistent (HCV) and an acute lytic virus (DENV) deal with the host cell.
Research Team Members
The research areas described below apply to HCV and DENV that we study in parallel in order to identify principles that are either unique to each virus or that might apply to viruses more general.
I. Biogenesis and 3D structure of the membranous replication compartment
Replication of plus-strand RNA viruses occurs in close association with intracellular membranes. We have earlier shown that Dengue virus (DENV) induces invaginations of ER membranes (Welsch et al., Cell Host & Microbe 2009) whereas HCV induces double-membrane vesicles that appear as protrusions from the ER (Romero-Brey et al., Plos Pathogens 2012). By using a combination of light and electron microscopy techniques we study the 3D architecture of these virus-induced membrane alterations and try to identify functional sub-compartments. We combine these data with functional and mechanistic analyses in order to understand the cell biology underlying the biogenesis of these membranous replication compartments. Finally, we aim to establish in vitro reconstitution systems allowing to understand the biophysics underlying induction of membran curvature.
II. Identification of host cell factors regulating the viral replication cycle
By using high throughput screens we want to identify host cell dependency or restriction factors. We use either whole virus-based genome-wide screens or distinct subscreens such as kinases (see e.g. Reiss, Rebhan et al., Cell Host & Microbe 2011).
III. Virus assembly
Assembly of virus particles requires the concerted action of viral and host cell proteins as well as distinct lipids. We have earlier shown that HCV assembly is tightly linked to lipid droplets and proposed several mechanisms how infectious virus particles might form (reviewed in Bartenschlager et al., Trends in Microbiology, 2011). In addition, we have determined the lipidome of HCV (Merz, Long et al., Journal of Biological Chemistry, 2011). Building on these results we now want to determine how the different steps of the assembly process are coordinated, which cellular proteins are required for that and how virus particles are released from the cell. For this we employ high resolution microscopy methods including electron tomography and live cell imaging.
IV. Innate immune responses against viral infection and viral countermeasures
Virus infections are sensed by pattern recognition receptors leading to, amongst others, the expression of interferons. Viruses in turn have developed strategies to cope with this innate antiviral response. We have earlier shown that HCV blocks signalling pathways by cleaving the adaptor protein MAVS (Meylan et al., Nature 2005) and obtained evidence that HCV persistence might be facilitated by the stochastic nature of the interferon response (Bauhofer et al., Gastroenterology 2012). We now want to establish mathematical models describing this stochasticity in order to identify rate-limiting steps. In addition, we want to characterize the antiviral mechanism of Interferon-stimulated genes (Metz et al., Hepatology 2012) and the exploitation of virus-induced stress response to sustain persistence (Ruggieri et al., Cell Host & Microbe 2012). Finally, we aim to exploit our knowledge gained with studies of HCV in order to establish an immuno-competent mouse model.
V. Development of antiviral drugs, broad-spectrum antivirals and drug resistance assays
In case of HCV, numerous antiviral drugs are in clincial development. For several of them the mode-of-action is unclear and we aim to clarify this (see e.g. Steinmann et al., Hepatology 2007). In addition, we aim to develop broad-spectrum antiviral drugs, which is of high importance especially for ‘emerging’ viruses. Here, we use the knowledge gained during our studies of HCV and DENV. Finally, we are setting up phenotypic resistance assays, which is of relevance given the recent approval of HCV-specific NS3 protease inhibitors.