Structure of a trypanosome receptor solved for the first time
A recent paper in Proceedings of the National Academy of Sciences from Dr Matt Higgins' group, in collaboration with Professor Mark Carrington at the University of Cambridge, has revealed the structure of a crucial receptor found on the surface of trypanosomes .
Structure of the haptoglobin-hemoglobin receptor found on the trypanosome surface
The structure is the first of any trypanosome receptor and provides molecular insight into the receptor’s role in mediating both nutrient uptake and innate immunity in a delicate balancing act essential for parasite survival.
Trypanosomes are parasites that cause sleeping sickness in humans and nagana in cattle, leading to misery and disease in large parts of Africa. They live in the blood of patients where they must obtain nutrients but also avoid detection by the human immune system.
A highly specialised protective surface coating made from the VSG protein prevents detection of the parasites by human antibodies. Within this coat are receptor proteins that allow nutrient uptake, including the haptoglobin-hemoglobin receptor (HbHpR).
This receptor plays two keys roles during trypanosome infection. It is used by the parasite to acquire heme from the haptoglobin-hemoglobin complex, providing an essential nutrient to the dividing cell. HbHpR is also a component of the innate immune response of humans to trypanosome infection, functioning as the primary receptor by which trypanosome lytic factor (TLF1) - a component of human serum that causes trypanosomes to swell and die – is taken up.
The newly discovered structure of HpHbR provides an explanation for how human-infective trypanosomes avoid killing via TLF1 whilst retaining the ability to take up essential nutrients.
The structure reveals that the receptor protrudes above the protective VSG layer, allowing recognition of its ligand, but leaving it exposed to immune detection.
However, a single amino acid change in the receptor – as found in the human infective trypanosome species T. b. gambiense– abolishes binding of TLF1 but permits continued haptoglobin-hemoglobin binding. This change enables the parasite to survive the effects of TLF1 by limiting lytic factor uptake.