Structural studies of Plasmodium PIR proteins and their interactions with human inhibitory immune receptors

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Malaria is one of the most deadly diseases to affect mankind, leading to around half a million deaths and hundreds of millions of cases each year. It is caused by infection with tiny Plasmodium parasites. These single celled organisms are injected into affected individuals through the bite of an infected mosquito and develop and divide within the human liver and blood. The symptoms of the disease occur during the blood stage of infection. Here the parasites invade human blood cells and divide within them, with one parasite entering each blood cell and ten to twenty emerging two days later. An intracellular life style provides these parasites with major advantages. Pathogens within the blood are under constant attack from the human immune system and concealment within a host cell allows them to avoid detection. However, Plasmodium send a small number of parasite molecules to the surfaces of infected red blood cells. This is a dangerous strategy, as it risks their detection, and so these proteins have critical functions in helping the parasites to survive within the infected human. To help avoid detection, these surface molecules are not present in single copies, but as diverse protein families. This allows the parasite to respond when the human immune system learns to recognise one of their surface molecules by switching to use a different, unrecognised molecule.The most commonly found proteins on the surfaces of malaria-infected blood cells are the PIR proteins. All types of Plasmodium parasites studied so far produce PIRs, including the major human-infective malaria parasites, Plasmodium falciparum and Plasmodium vivax. Although we know remarkably little about the roles that these proteins play during infection, recent studies have given new and tantalizing clues. In one such study, malaria infection was characterised in mice. Mouse malaria can either be acute, leading to severe illness, or chronic, with long term, low level disease. Whether the malaria episode became chronic or acute correlated with which of the PIR proteins was expressed. In parallel, two different groups of Plasmodium falciparum PIR proteins (also known as RIFINs) were found to bind to human molecules know as inhibitory immune receptors. These receptors dampen the human immune response by reducing the effects of immune cells, potentially reducing the capacity of these cells to recognise infectious agents. Indeed, binding of RIFINs to the human inhibitory immune receptor, LILRB1, reduced antibody production, which will make the immune system less responsive. These findings suggest the exciting hypothesis that the PIR proteins dampen the human immune system, reducing its ability to detect and destroy the parasite. This would aid parasite survival and transmission between individuals, causing more malaria cases. Remarkably, no-one knows what a PIR protein looks like or how they bind to inhibitory immune receptors. This makes it extremely challenging to understand how they function and how they affect the human immune system. Without this insight it is hard to classify the hundreds of PIR proteins into groups or to work out which human receptor each group binds. Finally, without knowing their structures, we cannot understand which bits of the PIRs are similar and which are variable. If we wish to train the immune system to recognise all PIR proteins, then we need to be able to find their invariant parts. This funding will therefore allow us to address these questions, understanding the structures, functions and variability of the PIRs. This will help us to understand the role of the most commonly found protein on the surface of the malaria-infected blood cells, showing us how they modulate the immune system and revealing whether we can find an invariant site on these molecules which we can target therapeutically to as part of our quest to destroy this deadly parasite.