Marc Dionne and J Krishnan propose to engineer an immune response in order to understand better the imperfections of immune systems
Immune systems are crucial to preventing infections and maintaining health in all organisms. Their importance can hardly be overstated; the COVID-19 pandemic has highlighted the serious consequences which ensue when immune systems are either not strong enough or are overactive. But how can this balance be struck? All immune reactions harm the host as well as the invader; for an immune system to work well, the response must be strictly controlled, preserving the health of the host while controlling the infection. Can we engineer a system that can control bacterial infection and keep the host healthy?
This project is a collaboration between myself and Dr Krishnan. I am an experimental immunologist; for more than 20 years, I have studied how fruit flies defend themselves against bacterial infection. Dr Krishnan is a theoretical biologist studying how cells and tissues can process information and respond to stimuli. The question of how an animal can perceive and respond appropriately to infection is a common interest of ours. Together, we realised that engineering approaches, combining experimental approaches in fruit flies with computational modelling, would be an interesting way to address the fundamental question of how immune systems can balance eliminating infection and keeping the host healthy.
Our approach is based on an observation I made several years ago. I was interested in how fruit flies would defend themselves against a specific class of bacteria, the mycobacteria. Some mycobacteria are important causes of human disease – they cause tuberculosis and leprosy – but most kinds of mycobacteria do not cause disease because they cannot escape killing by our immune response. I found that fruit flies exhibited almost no immune response to mycobacteria: ordinarily, in flies or humans, the immune response is activated by sensing invading organisms, but the fruit fly immune system was almost unable to sense mycobacteria.
This meant we could ‘install’ an entirely new immune system in the fruit fly for sensing and killing mycobacteria. Dr Krishnan and I designed a system, putting together a receptor from humans that can sense mycobacteria, several synthetic peptides that others have found to be able to kill mycobacteria, and an enzyme from another bacterium that can degrade the mycobacterial molecule sensed by the receptor (so the system can turn off once the mycobacteria have been killed). With this grant from the Leverhulme Trust, we will now implement this system in reality, test how well it works, and determine whether each part is essential and can be improved.