Jump to content
Powered by

Viruses are the major cause of myocardial diseases

About 500,000 people in Germany suffer from dilatative cardiomyopathy (DCM). Viral infections are the major cause of this myocardial disease. Its molecular and cellular mechanisms are being investigated in a transregional SFB project at the University of Tübingen.

Viral infections of the myocardial muscle are of major clinical importance. At the same time, little research is being done on such infections. That is why the DFG established the SFB Transregio 19 research centre in 2004. Six hospitals and scientific institutions are combining their scientific skills in order to investigate the basic mechanisms of this disease as well as to develop new analytical, diagnostic and therapeutic methods. The team headed by Prof. Dr. Karin Klingel of the Department of Molecular Pathology at the University Hospital Tübingen is also involved in the project and is investigating the influence of host-virus interactions on the immune system.
Prof. Dr. Karin Klingel (Photo: private)

An important aspect is the transition from acute to chronic viral myocarditis which eventually leads to DCM. This transition is well described for coxsackie virus infections. The virus directly attacks the myocardial cells. In the mouse model, the animals develop acute myocarditis six to seven days after initial virus contact. If the immune system is able to control the infection, complete cure can be expected within a few weeks. However, occasionally, the virus persists and cannot be removed from the organism which means that the acute myocarditis becomes chronic. “This also happens in humans. We are now trying to find out why the immune system sometimes succeeds in eradicating the virus and sometimes does not,” said Klingel. The researchers assume that an inefficient immune control is the cause of the inability to protect the body against such viruses.

Coxsackie virus - an enterovirus with disease potential

“We assume that the course of the viral infection is controlled by genetic factors through the immune response. We have conducted investigations on mice and found cytokines and chemokines that are released by the dendritic cells of the immune system in response to the virus infection. These –kines are important regulators of the immune response,” said Klingel who focuses in particular on CTGF (connective growth factor) and osteopontin, two molecules that are important in the early phase of the immune response. “CTGF and osteopontin govern the extracellular matrix which is reorganised following viral infection in such a way as to promote the development of a fibrosis in the myocardial muscle,” affirms Klingel.
Acute parvovirus B19 myocarditis; heart tissue (autopsy); determination of Parvovirus B19 DNA in the endothelial cells of small arterial and venous vessels using radioactive in-situ hybridisation.
Acute parvovirus B19 myocarditis; heart tissue (autopsy); determination of parvovirus B19 DNA in the endothelial cells of small arterial and venous vessels using radioactive in-situ hybridisation.
However, not all viruses that are found in the myocardial muscle pursue the same infection strategy. Parvovirus B19, for example, only infects endothelial cells that coat the inner wall of the blood vessels. The mechanisms with which this virus induces myocarditis are still completely unknown. “In 2002, we found purely accidentally that this virus causes myocarditis. We were able to identify the virus by way of in-situ hybridisation in a patient biopsy that had the clinical picture of a cardiac infarction,” said Klingel who is now working hard to find out more about the course of the infection.

In-situ hybridisation identifies artefacts

Over the last few years, the Tübingen researchers have examined several thousand myocardial muscle biopsies using in-situ hybridisation. They have also further developed and optimised the technology. In the meantime, the researchers know that some of the viruses that are known to infect the myocardial muscle only mirror the infection of blood cells. “Myocardial biopsies can be contaminated with blood that contains influenza or adenoviruses. If the viral nucleic acids are subsequently amplified with PCR, false positive results are often obtained.”

Research is expanded

Projects that are part of SFB Transregio 19 can be funded for up to twelve years. The first four-year period has just come to an end and Klingel has submitted a follow-up application because of the promising results obtained in the first funding period. The new application will be evaluated in March 2008. “We have expanded the project and taken a new partner onboard. Prof. Dr. Meinrad Gawaz from the Department of Cardiology and Cardiovascular Diseases at the University Hospital of Tübingen pursues two approaches. First, he is investigating the influence of thrombocytes and progenitor cells on the development of myocarditis. Second, Gawaz is investigating the mechanisms that trigger the reorganisation of the extracellular matrix in patients suffering from myocarditis,” said Klingel.
Microsopical photo of heart tissue
Endomyocard biopsy of a normal heart (HE staining).
Klingel herself is planning to focus more on the molecular relationships in the early phases of the immune response triggered by parvovirus B19 and coxsackie viruses. “This requires large quantities of biopsies. We are unable to cover the demand with our current collaborators and are happy that Professor Gawaz provides us with easier access to the required material. And this is an enormous advantage,” highlights Kingel. The work on the mouse model is also important and Klingel plans to further pursue this project in cooperation with Dr. Katja Kotsch from the Charité in Berlin. The purpose of their collaboration is to investigate the activity of the non-killer cells (NKZ) of the immune system. “We have already been able to show that myocarditis is more severe when the NKZ are blocked,” explained Klingel.

A whole plethora of molecular genetic reaction chains has to be clarified

The more the scientists know about the immunological factors involved in host-virus interactions, the easier it is to develop new therapeutic concepts. These might include therapies involving substances that block or enhance a certain step of the immune response. Another option might be the intervention in certain regulatory mechanisms. One thing is sure: It will not be easy.

“There are no diagnosis or therapy guidelines because the event is extremely interlinked and multifunctional. Targeting one point might have many effects and it is not known what and where something will happen,” said Kingel. She and her colleagues hope that the next SFB work package will help them get a big step closer to identifying the overall context.

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/viruses-are-the-major-cause-of-myocardial-diseases