Why is the innate immune system so important? The human immune defence consists of an innate and an adaptive branch. The innate immune system works through a series of redundant and unspecific mechanism to inhibit viral replication, whereas the adaptive immune system can recognize and destroy specific pathogens. It does so through production of specific antibody's and cytotoxic T-cells. Once fully operational the adaptive immune system will remove all virus particle and destroy infected cells and thus cure the infection. However, the establishment of an adaptive immune response takes 5 to 7 days, during this critical period it is the innate immune system that protect us.
Interferon’s control innate immunity. Interferon’s are cytokines (small hormone like proteins) which control the innate immune response to viral infections. They are popularly speaking the body’s own “alarm system”. If a cell is infected by a virus, the cell will start to produce interferon within one to two hours. The newly produced interferon will bind to receptor complexes found on the cell surface of neighbouring cells and activate this receptor. The activation of the receptor leads to activation of transcription factors which induce the synthesis of a number of antiviral genes. Thus in effect IFN is warning the cell of the coming virus and starting the defensive mechanism. There exist 3 groups of interferon’s, Type 1 (IFN a/b), type 2 (IFN g) and type 3 (IFN-lambda); type 1 interferon’s provide the direct antiviral effect and type 2 is responsible for mobilization of the adaptive immune system. Type 3 or IFN-lambda is a newly discovered type of interferon and their precise role in the antiviral defence is not yet clear.
Structure and antiviral activity of the OAS family of proteins. The OAS protein family is a classical antiviral protein. It recognizes viral RNA structures and initiates an antiviral response. We are studying both the structure and the function of this protein. We have developed methods to assay the effect of the OAS proteins upon viral replication and are currently investigating the mechanism behind the antiviral effect. We are also interested in how OAS recognizes specific viral RNA structures and avoid cellular RNA.
Interferon lambda signalling. We are investigating how Interferon Lambda binds to it cognate receptor and initiate signalling. We have recently solved the crystal structure of interferon lambda and are now mapping the interaction of interferon lambda with the receptor. Interferon Lambda target specific tissues in the body (as opposed to type I Interferon which targets all cells), we are currently investigating the specificity of interferon lambda and the advantages this can have in clinical use.
Designing new interferon lambda mutants with improved therapeutic potential. We will use our knowledge of the interferon lambda structure and how it signals to design new versions of interferon lambda with increased antiviral activities.
Our laboratory applies a number of state of the art techniques from “hard core” structural biology to growing viruses in cell culture. Students will have the unique opportunity to work in a highly interdisciplinary environment and to lean a number of useful techniques. In addition to the techniques mentioned below we are also using most standard molecular biology and biochemistry techniques.
Structural biology. We are primarily using X-ray crystallography for the study of macromolecular structure, particularly structures of proteins from the innate immune system.
Viral replication. We have a fully equipped Biosafty level II laboratory. Interested students can learn basic techniques in growing viruses and measuring viral replication rates. Furthermore we have established assays to measure antiviral activities that we use to test potential antiviral compounds.