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.
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.
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.
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).
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.
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.