One of the most iconic cellular interactions is that between sperm and eggs. Surprisingly, the molecules involved in this cellular interaction are not well understood. To tackle this question, we used our approaches to discover Juno: a receptor displayed on the surface of eggs that directly interacts with the sperm protein Izumo1 and is essential for mammalian fertilisation.
The egg is presented with a delicately-balanced problem: it must be fertilised to survive and propagate the next generation, and yet it must rapidly become unreceptive to subsequent sperm to prevent the creation of a non-viable polyspermic embryo. We showed that the Juno receptor was rapidly lost from the egg membrane after fertilization providing a molecular mechanism for this phenomenon.
Bianchi et al. "Juno is the egg Izumo receptor and is essential for mammalian fertilization" Nature 508 p483 2014.
Erythrocyte invasion by the parasite that causes severe malaria
The parasites that cause malaria recognise and invade our red blood cells, a process that is essential for malaria pathogenesis.
Red cell recognition involves direct interactions between parasite surface proteins and host receptors. By applying our methods, we showed that a host receptor called “basigin” interacted with a parasite protein called RH5. With collaborators, we showed that this interaction was both essential and universally required by the parasite for invasion. The consequence of this discovery means that RH5 is now being explored a malaria blood stage vaccine target.
Crosnier et al. "Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum" Nature 480 p534 2011.
Genome-led vaccine target identification for neglected tropical diseases
There are no licenced vaccines for many of the infectious diseases that threaten the lives and livelihoods of people living in some of the most impoverished regions of the world.
Despite the fact that we have full genome sequences for all the major pathogens, there remains a desperate shortage of vaccine candidates. We have systematically tested our panels of extracellular pathogen proteins in preclinical models to identify new vaccine targets for these diseases. Our discoveries have started to provide hope that vaccines can be developed for parasitic diseases where vaccination was previously thought to be very challenging or impossible.
Autheman et al. "An invariant Trypanosoma vivax vaccine antigen induces protective immunity" Nature 595 p96 2021.
An interaction network of human leukocyte receptors
The human immune system is composed of a distributed network of many different migratory cell types, each with specialised roles that must be coordinated to mount an effective immune response. How do these cells exchange information so that they behave appropriately to destroy pathogens and yet leave healthy cells untouched? We already know of many important instructive signals are initiated by direct interactions between receptors displayed on the surface of these cells, although a comprehensive map of these interactions was missing.
Using our protein interaction technologies, we systemtically mapped these interactions which we hope will lead to the development of new drugs that target these interactions.
Shilts et al. "A physical wiring diagram for the human immune system" Nature 608 p397 2022.
The origins of P. falciparum malaria
Malaria has probably been responsible for more human deaths than any other disease. The origin of the parasite that causes this infection - Plasmodium falciparum - is therefore of great interest. We now know that P. falciparum resulted from a zoonotic event - a series of molecular changes in the parasite which originally infected animals so that it could infect humans. What were these changes and how did they permit infection of humans? In 2019, we published a study that provided a plausible molecular pathway for the origin and evolution of P. falciparum which has caused one of the greatest health problems known to mankind.
Galaway et al. "Resurrection of the ancestral RH5 invasion ligand provides a molecular explanation for the origin of P. falciparum malaria in humans" PLoS Biology 2019.
Listen to BBC Inside Science podcast who covered this story. [Relevant section starts at 20min 15sec]
The Covid-19 pandemic
We have used our human receptor resources and extracellular protein interaction assays to contribute to the fight against the SARS-CoV-2 pandemic. This has included investigating proposed new receptors for the SARS-CoV-2 virus and the identification of novel host factors.
Videos of our research
See our full publication list by year