Signalling Molecules Produce Defence Reactions Against Viral Infections

All organisms are able to spontaneously defend themselves against viruses.

The innate immune system recognises intruders and releases signalling molecules such as interferons in response to the presence of viruses. Up until a few years ago, the pharmaceutical industry had predominantly focused on the investigation of type I interferons. However, type I interferons are also known to cause undesired side effects since they trigger alarms in almost all types of body tissue irrespective of the infection site. Dr. Markus Mordstein has spent the last four years as a doctoral student at the Speman Graduate School of Biology and Medicine (SGMB) at the University of Freiburg investigating the previously relatively unknown interferon lambda. He has been able to show that this molecule has similar protective functions to type I interferons, and he has also found that it is far more selective in terms of the site where it exerts its effect.

The innate immune system comprises cells and mechanisms that defend the host from being infected by organisms in a non-specific manner. It is made up of mechanical barriers such as the blood-brain barrier and also has the ability to recognise certain structures on the surface of an intruder. Once the innate immune system has discovered a viral or bacterial intruder, the cells release signalling molecules such as interferons. Interferons are proteins that are able to bind to specific receptors on the surface of other cells. This binding triggers a signalling cascade inside the cells, leading to the activation of hundreds of different genes. The cells that are informed of the presence of pathogens by the interferons then induce a defence reaction against the intruders: a buzz of activity occurs at the infection site, an inflammatory response that ideally leads to the elimination of the intruder before disease develops. This is why interferons are important alarm molecules. "The interferon system mediates a very early immune response. Many different interferons are released within a few hours of infection," said Dr. Markus Mordstein who completed his doctoral thesis in December 2010 at the Institute of Medical Microbiology and Hygiene in the Department of Virology under the structured PhD programme offered by the SGBM graduate school of the University of Freiburg. "The question arises as to whether different interferons have different functions."

Is interferon lambda really needed?

Up until a few years ago, researchers had predominantly focused on type I interferons, which are indispensable proteins for defence reactions. When Mordstein commenced his degree thesis in 2006 in Professor Dr. Peter Stäheli's department, interferon lambda had just been described. It is now known that interferon lambda activates different receptors from those targeted by type I interferons. Back then, the detailed function of the molecule was hardly known and researchers were attempting to answer the question as to whether interferon lambda was actually necessary for an immune response to occur. Stäheli's group of researchers were extremely lucky to have available in their laboratory a knock-out mouse strain that possessed a defective interferon lambda receptor gene and hence lacked functional IFN-lambda receptors. The cells of such mice are therefore unable to recognise and react to an interferon lambda signal. In both his degree and doctoral thesis Mordstein was tasked with finding out whether the reaction to infections caused by influenza A viruses, for example, differs between mice lacking functional IFN-lambda receptors and normal mice. "We therefore focussed on finding an answer to the question as to whether mice really needed interferon lambda to defend themselves against viral intruders," said Mordstein going on to add "and if this was the case, what exactly do they need it for?"

Type I interferons carry out their function in all the tissues of an organism. Mordstein was able to show in several experiments that interferon lambda only played a role in epithelial tissue, which is found for example in the gastrointestinal tract, the lungs or the skin. Epithelial tissues are the first tissues to come into contact with a pathogen. The researcher found that interferon lambda provided extra protection when used with the type I interferons. The finding that this molecule is highly tissue-specific is currently of particular interest. A variety of human clinical studies are currently being carried out to test the use of interferon lambda as an alternative to type I interferons for the treatment of hepatitis C virus infections. “Although we have been able to show that interferon lambda does not play a role in the mouse liver because it has no interferon lambda receptors, we have also found that these results cannot be directly transferred to humans.” The researchers are now hoping to come up with results that show that interferon lambda is as effective as type I interferons in combating hepatitis C viruses and that it is associated with fewer side effects due to its high tissue specificity.

Is interferon lambda more important than its relatives – at least in certain cases?

The researchers have found out that interferon lambda plays a particular role in the gastrointestinal tract. Mordstein and his colleagues investigated whether the molecules mediate defence reactions in people suffering from rotavirus infections. Rotavirus is the most common cause of severe diarrhoea among children in developing countries. The results have shown that type I interferons play hardly any role at all in destroying the rotaviruses, but in contrast the same results revealed that interferon lambda renders the epithelial cells of the gastrointestinal tract resistant to viral infections. If the receptor of the signalling molecule is defective, the strength of the infection increases dramatically. “In summary, we can say that interferon lambda has a complementary effect to the interferon type I system,” said Mordstein. “However, when certain viruses intrude the gastrointestinal tract, interferon lambda seems to play a more important role than its type I relatives.”

While he was doing his doctoral thesis, Mordstein became a real specialist in the field of interferon lambda research, which until that point had been seen as a rather exotic field of research. The PhD student has since been invited to present his findings at renowned conferences and he also acts as a reviewer for journals that publish articles on this issue. In December 2010, he was awarded the SGBM’s newly established Gluecksohn-Waelsch Award for his achievements. Despite all this success and also the many post-doctoral positions he has been offered, Mordstein does not want to continue university research. “I think there is a lot of insecurity in university work, especially as far as permanent positions are concerned,” said Mordstein who therefore decided to accept a position in the microbiology department at Novartis Pharma in Switzerland.

Source: http://www.bio-pro.de/