Professor Tuomas Knowles in Cambridge before the coronavirus lockdown
Professor Tuomas Knowles and his colleagues are developing a new approach to help better understand the body’s defences against SARS-CoV-2, and ultimately support the development of reliable antibody tests and vaccines.
To do this, they are using new technology to investigate the key protein interactions involved in the biology of the SARS-CoV-2 virus (the coronavirus involved in the current pandemic). “Understanding these protein-protein interactions is crucial to our ability to evaluate, for example, whether a potential vaccine will work effectively,” explained Knowles. The team are especially interested in the humoral immune response, in which antibodies produced by B cells (a type of white blood cell) attack extracellular microorganisms.
Knowles and his team are collaborating with Fluidic Analytics, a spin-out company that has developed a unique technology platform based on research originally performed in his research group. This platform allows researchers to examine protein interactions directly in serum or other solutions, rather than the traditional method of using surfaces to probe protein interactions.
“Using traditional surface methods, it’s more challenging to get the right answer about how proteins are interacting, especially in complex systems,” said Knowles. “Our microfluidic technology allows us to investigate protein-protein interactions as close to their biological settings as possible, without having to attach any of the proteins to surfaces.”
To successfully initiate an infection, all viruses need to overcome the cell membrane barrier. Coronaviruses use a spike protein to bind to a receptor on the target cell and facilitate the entry of the virus. Working with researchers at Fluidic Analytics, the team have been focusing on the spike protein of SARS-CoV-2, and the ability to detect antibodies which can interfere with the function of this viral protein.
The researchers are employing an analytical approach developed by research fellow Dr Georg Meisl and implemented by postgraduate student Catherine Xu, which allows them to investigate how the spike protein interacts with cellular receptors, and how this process can be modulated. These protein-protein interactions can be quantified, classified and analysed. Another PhD student, Matthias Schneider, has been instrumental in developing a lot of the chemistry that allows the measurements to be performed. “We have also been very fortunate to have a great collaboration with the Department of Surgery here in Cambridge, in particular with Dr Vasilis Kosmoliaptsis, in demonstrating the applicability of these assays to patient samples," said Knowles.
Understanding how to safely prevent the spike proteins from binding to the target cell receptors will be key in developing effective vaccines. “These measurements will pave the way to an understanding of how immunity against the virus develops, and whether exposure to other viral infections can be protective,” said Knowles.
Using the same technology, Knowles and his group have also begun working with a team of clinicians to investigate why different people have different immunological reactions to the virus. “We are working hard to find out why some patients get very ill when exposed to the virus, while others experience only mild symptoms,” he said. “We are particularly excited about our collaboration with the University Hospital in Zurich, where we have the chance to integrate this approach with world-leading research efforts on the pathology and serology of the virus, led by Professor Adriano Aguzzi.”
Knowles and his group have previously successfully used these innovative techniques to probe the body’s natural defences against the aberrant protein aggregation characteristic of Alzheimer’s disease. “We’ve been working for many years on developing ways of probing protein-protein interactions in solution under native conditions, as close to their biological settings as possible. All life depends on these interactions.”
Knowles is delighted that they are able to use their experience in this area to help in the current fight against COVID-19. “Everybody’s trying to see what they can do to help, and we’re keen to do our part.”