Research leader: Prof Wolf-Dieter Schubert
Co-investigator: Dr Precious Motshwene
Structural elucidation of molecular mechanisms underlying infectious diseases and the host immune response
Humans like animals, plants and even microorganisms are at all times at risk of infection. To protect themselves from infection, organisms have developed a multitude of defensive strategies that in combination form the respective immune systems. Pathogens, however, evolve alongside their hosts creating ever more complicated mechanisms of overcoming or evading the immune system of their targeted host.
Our aim is to understand this molecular arms race between pathogen and host at the molecular and atomic level with the eventual aim of developing drugs to combat infections. We do this by isolating the corresponding virulence factors as well as their target molecules, crystallizing individual proteins or complexes and solving their crystal structures. We also investigate elements of the immune system and their interaction with either pathogen derived molecules or up- or downstream elements of the same signalling cascade. In addition to the structural analysis by X-ray crystallography, electron microscopy or small angle X-ray scattering, we also characterize the protein-protein or protein-ligand complexes by a range of biophysical techniques such as surface plasmon resonance spectroscopy, isothermal titration calorimetry and related methods.
To test the knowledge we have gained from the structural and molecular work, we incorporate potential modifications into the genome of the corresponding organisms to test whether we can up- or down-regulate particular signalling events at a cellular or even organismal level.
All results are published in peer-reviewed publications. Crystal structures are deposited with the Protein Data Bank for universal free access.
Our aim is to investigate communicable diseases at the molecular and atomic level. The methods we use are primarily structural biology and biophysical analysis. Individual projects will often involve two molecular components, one from the infecting organism (the virulence factor) as well as the host target of the virulence factor. The project then entails isolating the two components and purifying them to near absolute levels to avoid incorrect interpretations based on interfering interactions. On the one hand, proteins and protein complexes will be crystallized and their three-dimensional structure will be elucidated using X-ray crystallography and related techniques. On the other hand, protein-protein interactions will be analysed using biophysical techniques such as surface plasmon resonance spectroscopy or isothermal titration calorimetry to understand how specific and tight the interaction is – in particular relative to related physiological interactions . Where possible, insights and observations from the describe analyses will be incorporated into cellular or animal models to determine the importance of any one particular molecular interaction.
Virulence of the following organisms are currently being investigated:
Interacting molecules or molecules of innate immunity derive from:
Homo sapiens (humans)
Mus musculus (mice)
Ovis aries (sheep)
Bos taurus (cattle)
1. Prof. Keith Ireton, University of Otago, Dunedin, New Zealand.
2. Dr. Frank von Delft, University of Oxford, Oxford, United Kingdom.
3. Dr. Joop van den Heuvel, Helmholtz-Centre for Infection Research, Braunschweig, Germany.
4. Prof. Carsten Kirschning, University of Duisburg-Essen, Essen, Germany
5. Prof. Nico Gey van Pitius, Faculty of Health Sciences, University of Stellenbosch, South Africa.
6. Dr. Colin Kenyon, Council for Scientific and Industrial Research, Pretoria, South Africa.
7. Prof. Nick Gay, University of Cambridge, Cambridge, United Kingdom.
8. Prof. Clare Bryant, University of Cambridge, Cambridge, United Kingdom.
9. Prof. Alex Weber, University of Tübingen, Tübingen, Germany.