Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system

Sleeping sickness is caused by trypanosome parasites, which infect humans and livestock in Sub-Saharan Africa. Haem is an important growth factor for the parasites and is acquired from the host by receptor-mediated uptake of haptoglobin (Hp)–haemoglobin (Hb) complexes. The parasite Hp–Hb receptor (HpHbR) is also a target for a specialized innate immune defence executed by trypanosome-killing lipoprotein particles containing an Hp-related protein in complex with Hb. Here we report the structure of the multimeric complex between human Hp–Hb and Trypanosoma brucei brucei HpHbR. Two receptors forming kinked three-helical rods with small head regions bind to Hp and the β-subunits of Hb (βHb), with one receptor at each end of the dimeric Hp–Hb complex. The Hb β-subunit haem group directly associates with the receptors, which allows for sensing of haem-containing Hp–Hb. The HpHbR-binding region of Hp is conserved in Hp-related protein, indicating an identical recognition of Hp–Hb and trypanolytic particles by HpHbR in human plasma. Trypanosomes, responsible for sleeping sickness, acquire haem through binding haptoglobin(Hp)–haemoglobin(Hb) complexes in human blood. Here Stødkilde et al. determine the structure of human Hp–Hb in complex with the Hp–Hb receptor from T. brucei and show that the recognition elements are shared by a protein complex on the surface of a trypanolytic lipoprotein particle.