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Systems biology and hepatitis C research

The international research project SysPatho aims to advance the understanding of HCV (hepatitis C virus) infections using systems biology approaches. The goal of the project coordinated by Universität Heidelberg is to develop new mathematical and computational methods to reconstruct HCV-infected hepatocytes, which can be used to identify new drug targets and help treat this dangerous disease.

Hepatitis C viruses. Electron microscope image, negative staining. © German Cancer Research Center

According to World Health Organization (WHO) estimates, more than three percent of the world’s population are infected with hepatitis C virus (HCV). The number of infected people is particularly high in East Asia, tropical Africa and South-America as well as in southern and southeastern Europe. Around 500,000 people in Germany are infected with HCV, but a high number of incidents goes unreported as many HCV sufferers are unaware of their infection and disease because the infection is often asymptomatic, at least at the outset, and inflammation of the liver is not painful.

Medical and health policy challenges

The fact that the infection is often asymptomatic and goes undetected for a long time makes hepatitis C a treacherous disease. If left untreated, chronic infection can lead to scarring of the liver and ultimately to cirrhosis and liver cell cancer (HCC, hepatocellular carcinoma). HCC is one of the most common types of cancer in men. It is difficult to treat and has a fatal outcome in many cases. In Germany, the incidence of HCC-related diseases and deaths has increased alarmingly over the last decades.

While several vaccines have been developed for the prevention of hepatitis B virus infection, no vaccine is available for the prevention of hepatitis C virus infection. It is difficult to develop vaccines for HCV due to the virus’s extreme genetic heterogeneity. HCV infection is usually treated with drugs – often combination therapies involving interferon alpha and other antiviral agents - to eliminate the virus from the blood. Although progress has been made in the treatment of HCV infection (see BIOPRO article “Breakthrough in the treatment of hepatitis C, 13th April 2011; in German only), the virus is far from being besieged. It is genetically very variable and is characterised by a high mutation rate. Doctors frequently come across patients who are infected with a virus genotype which is virtually or completely insensitive to existing drugs. In addition, many patients experience severe adverse effects and treatment needs to be abandoned. Further research is necessary in order to be able to get the medical and health-political issues associated with HCV infections under control.  

An international systems biology approach

Researchers at the Department of Infectious Diseases – Molecular Virology at Universität Heidelberg (director: Professor Dr. Ralf Bartenschlager) have long focused their research activities on hepatitis C infection and potential treatments. The researchers are also involved in a large international research project focused on investigating the dynamics of viral replication in liver cells and the interactions between HCV and its human host using a systems biology approach. Quantitative molecular biology methods are combined with methods from the fields of bioinformatics and systems sciences with the aim of developing a mathematical model that describes the major steps of HCV infection, the propagation of the viruses and the complex interactions with the host cells.

The “SysPatho” (also known as “PathoSys”) research project, which was initiated in October 2010 and is funded under the European Commission’s 7th Framework Programme for a period of four years, brings together eight academic and two industrial partners. The project is coordinated by Professor Dr. Roland Eils (from the German Cancer Research Center (DKFZ) and director of the BioQuant research centre at Universität Heidelberg) and Professor Dr. Lars Kaderali (at the Institute of Medical Informatics and Biometrics at Dresden University of Technology since November 2011; formerly at BioQuant).

HCV replication cycle in the human liver cell. © TU Dresden
In addition to the University and University Hospital of Heidelberg and Dresden University of Technology, the SysPatho research project also involves the INSERM in Paris (France), the Middle East Technical University in Ankara and Bahçeşehir Üniversitesi Foundation in Istanbul (Turkey), the ORT Braudel College in Karmiel (Israel), the St. Petersburg State Polytechnical University and the Institute of Cytology and Genetics of the Russian Academy of Sciences in Novosibirsk (Russia). Industrial partners – NovaMechanics Ltd. (Lefkosia, Cyprus), a company focused on in silico drug design, and Novosibrisk-based PBSoft, a start-up company focused on the extraction of knowledge from databases and literature – were brought on board with the objective of facilitating the transfer of knowledge into industrial and pharmaceutical application. In line with its broad-based international activities, SysPatho pursues an integrative multidisciplinary approach whose goal is to develop methods to analyse and integrate a wide variety of data from wet lab experiments (molecular biology, biochemistry), databases and biological literature and develop and apply new algorithms, mathematical models and systems analyses to reconstruct and study virus-host interactions from experimental data.

Cooperation between Russian and European researchers

The strong presence of Russian partners in a project funded under the 7th European Framework Programme might appear surprising as the EU – in contrast to agreements with Turkey and Israel – has not signed an association agreement with Russia. However, the 7th FP systems biology call is specifically aimed at strengthening the cooperation between European and Russian partners. Traditionally, Russia has a strong profile in mathematics and the theoretical sciences, and many problems faced by systems biologists in research projects such as SysPatho are similar to those faced in other areas to which Russian scientists have made outstanding contributions, including theoretical physics, mathematical systems theory, optimisations, control theory and graph theory. The partners hope that the close cooperation with Russian partners in the SysPatho research project will lead to new impulses and findings related to the development of dynamic models of virus-host interactions and to the analysis and calibration of these models. The researchers will discuss their latest findings at the SysPatho workshop “Systems Biology and Medical Applications”, to be held in St. Petersburg from 11th to 14th September.

Pathway of infection and the immunological defence in hepatic cells

Detailed knowledge about the infection pathway is absolutely crucial for developing mathematical models that realistically describe the complex interactions between the components involved in HCV infections. In addition, it is equally essential to identify as many as possible determinants – for example the viral nucleic acid and the proteins involved – in a quantitative and time-dependent manner. Hepatitis C virus is an enveloped, positive-sense single-strand RNA virus. When HCV infects a cell, the viral RNA enters the cytoplasm of the hepatocytes where it binds to the ribosomes (in the same way as messenger RNA) and is translated into a polyprotein. The polyprotein is cleaved into several proteins that are essential for viral replication, including its own RNA polymerase. By interacting with host-cell components, the viral proteins generate intracellular membranes, which are known as replication vesicles, where the viral RNA is protected against degradation by hepatic enzymes and against the cells’ immune signalling pathway and can be replicated: the polymerase uses the positive strand as a template to synthesise a complementary negative strand; this negative strand is used as a template for further positive strands.

Interaction of the molecular components that play a role in HCV infection. © Reiss et al. 2005; licensee BioMed Central Ltd.
Kaderali and other SysPatho researchers from Heidelberg and Dresden have determined the viral RNA and protein concentrations at short intervals throughout the entire HCV infection cycle in hepatocyte lines (Huh-7) and used these data to develop a computer model that effectively simulates the dynamics of the translation and replication of the HCV RNA genome. Using Huh-7 cells derived from a liver cancer patient who died 40 years ago, Bartenschlager and his colleagues successfully carried out the process of HCV infection in the laboratory for the first time ever. Huh-7 cells have the advantage of lacking the RIG-I receptor-coupled signalling pathway that medicates the recognition of viral RNA; this enables the researchers to analyse HCV replication in the absence of a host immune response. Cells fight off HCV infections in that RIG-I (“retinoic acid-inducible gene I”) is activated by binding to cytoplasmic double-strand viral RNA. This induces a signalling cascade that activates MAVS (“mitochondrial antiviral signalling protein”) and triggers an antiviral response. HCV can also impair or suppress the occurrence of a host immune response, for example by producing a protease that cleaves MAVS. The experimental and model predictions currently only cover a small section of the complex HCV-host interaction chain. Future research will also have to take into account the dynamics of the RIG-I-dependent immune response. The researchers have not yet dealt with the formation of the viral particles, their export from the cell and the infection of neighbouring cells. Rapid progress made in the generation of measurement data using state-of-the-art high-throughput methods, the theoretical basis of systems biology and the competence of the research groups involved, all contribute to the high level of confidence that the aims of SysPatho will be reached. The long-term goal of the researchers is to develop an “in silico” model of HCV infection and infected hepatocytes, which will enable predictions to be made about the course of infection under different conditions. The researchers hope that such insights will enable them to identify new drug targets and develop promising candidates for drugs with which it will eventually be possible to efficiently treat hepatitis C.
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