How does the trypanosome haptoglobin-hemoglobin receptor interact with nutrients and immunity molecules? Receptor structure to cellular mechanism.

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Trypanosomes are single celled parasites that cause significant disease in Sub Saharan Africa. They infect humans, causing African sleeping sickness. They also infect a variety of domestic animals, including cattle, leading to disease that reduces food production capability.Trypanosomes live and divide in the blood of their human or animal host. To survive in this environment they have a highly adapted cell surface. This allows them to take up nutrient molecules from the blood, which they can use as sources of energy or building materials as they grow and divide. However, it also puts them in peril. If they are recognised by antibodies, they can be detected and destroyed by the body's immune defences.The human body also contains several protein complexes called trypanolytic factors. If taken up into the parasite, these cause trypanosomes to burst and die. Species of trypanosome that can infect humans have developed ways to avoid trypanolytic factor uptake or to block the process that leads to lysis.How do the trypanosomes both take up nutrient molecules from the blood and to avoid recognition by antibodies? They are covered by a coat of a protein called VSG. This coat is dynamic with VSG molecules being taken up into the cell together with attached antibodies. The antibodies are degraded and the VSG returned to the surface. The parasite has the ability to express a large number of different VSG molecules, and they can switch which VSG they use to avoid detection by the immune system. The receptor proteins that are used to take up nutrient molecules must bind their cargos in the context of this VSG layer and yet avoid recognition by the immune system.In this proposal we will use a variety of different experimental tools to study one of these receptors - the haptoglobin-haemoglobin receptor (HpHbR). This receptor lies at the heart of a conflict for the parasite. It is involved in the uptake of HpHb into the trypanosome cell, from which the parasite obtains haem molecules to allow it to build its own cellular structures. But it is also a major route for the uptake of trypanolytic factors, leading to parasite death.We will use structural biology methods to understand, in molecular detail, how the receptor recognises its different cargos, including HpHb and trypanolytic factors. We will combine this with cell biology, allowing us to understand how ligand uptake occurs in the context of the parasite surface. This will be the first study that combines structural and cellular experiments to gain insight into a trypanosome receptor, revealing how the trypanosome surface is adapted to allow nutrient uptake while avoiding destruction by the body. It will also show how an uptake route for a toxin molecules functions. This is a route currently used by natural trypanolytic factors and has the potential to be subverted to allow drug and toxin molecules to be specifically targeted to this deadly parasite.