RESUMO
Only two trypanosome subspecies are able to cause human African trypanosomiasis. To establish an infection in human blood, they must overcome the innate immune system by resisting the toxic effects of trypanolytic factor 1 and trypanolytic factor 2 (refs. 1,2). These lipoprotein complexes contain an active, pore-forming component, apolipoprotein L1 (ApoL1), that causes trypanosome cell death 3 . One of the two human-infective subspecies, Trypanosoma brucei rhodesiense, differs from non-infective trypanosomes solely by the presence of the serum resistance-associated protein, which binds directly to ApoL1 and blocks its pore-forming capacity3-5. Since this interaction is the single critical event that renders T. b. rhodesiense human- infective, detailed structural information that allows identification of binding determinants is crucial to understand immune escape by the parasite. Here, we present the structure of serum resistance-associated protein and reveal the adaptations that occurred as it diverged from other trypanosome surface molecules to neutralize ApoL1. We also present our mapping of residues important for ApoL1 binding, giving molecular insight into this interaction at the heart of human sleeping sickness.
Assuntos
Apolipoproteína L1/metabolismo , Glicoproteínas de Membrana/química , Proteínas de Protozoários/química , Cristalização , Análise Mutacional de DNA , Humanos , Glicoproteínas de Membrana/genética , Ligação Proteica , Proteínas de Protozoários/genética , Trypanosoma brucei rhodesiense/química , Tripanossomíase Africana/imunologiaRESUMO
African trypanosomes have complex life cycles comprising at least ten developmental forms, variously adapted to different niches in their tsetse fly vector and their mammalian hosts. Unlike many other protozoan pathogens, they are always extracellular and have evolved intricate surface coats that allow them to obtain nutrients while also protecting them from the immune defenses of either insects or mammals. The acquisition of macromolecular nutrients requires receptors that function within the context of these surface coats. The best understood of these is the haptoglobin-hemoglobin receptor (HpHbR) of Trypanosoma brucei, which is used by the mammalian bloodstream form of the parasite, allowing heme acquisition. However, in some primates it also provides an uptake route for trypanolytic factor-1, a mediator of innate immunity against trypanosome infection. Recent studies have shown that during the evolution of African trypanosome species the receptor has diversified in function from a hemoglobin receptor predominantly expressed in the tsetse fly to a haptoglobin-hemoglobin receptor predominantly expressed in the mammalian bloodstream. Structural and functional studies of homologous receptors from different trypanosome species have allowed us to propose an evolutionary history for how one receptor has adapted to different roles in different trypanosome species. They also highlight the challenges that a receptor faces in operating on the complex trypanosome surface and show how these challenges can be met.
Assuntos
Imunidade Inata , Proteínas de Protozoários/genética , Receptores de Superfície Celular/genética , Trypanosoma brucei brucei/imunologia , Tripanossomíase Africana/imunologia , Moscas Tsé-Tsé/parasitologia , Animais , Evolução Biológica , Humanos , Estágios do Ciclo de Vida , Modelos Moleculares , Primatas , Proteínas de Protozoários/química , Proteínas de Protozoários/imunologia , Proteínas de Protozoários/metabolismo , Receptores de Superfície Celular/química , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Trypanosoma brucei brucei/genética , Trypanosoma brucei brucei/metabolismo , Tripanossomíase Africana/parasitologiaRESUMO
The haptoglobin-haemoglobin receptor of the African trypanosome species, Trypanosoma brucei, is expressed when the parasite is in the bloodstream of the mammalian host, allowing it to acquire haem through the uptake of haptoglobin-haemoglobin complexes. Here we show that in Trypanosoma congolense this receptor is instead expressed in the epimastigote developmental stage that occurs in the tsetse fly, where it acts as a haemoglobin receptor. We also present the structure of the T. congolense receptor in complex with haemoglobin. This allows us to propose an evolutionary history for this receptor, charting the structural and cellular changes that took place as it adapted from a role in the insect to a new role in the mammalian host.
Assuntos
Evolução Molecular , Hemoglobinas/química , Hemoglobinas/metabolismo , Proteínas de Protozoários/genética , Receptores de Superfície Celular/química , Receptores de Superfície Celular/metabolismo , Trypanosoma congolense/genética , Animais , Cristalografia por Raios X , Modelos Moleculares , Conformação Proteica , Receptores de Superfície Celular/genética , Moscas Tsé-Tsé/parasitologiaRESUMO
The haptoglobin-haemoglobin receptor (HpHbR) of African trypanosomes allows acquisition of haem and provides an uptake route for trypanolytic factor-1, a mediator of innate immunity against trypanosome infection. In this study, we report the structure of Trypanosoma brucei HpHbR in complex with human haptoglobin-haemoglobin (HpHb), revealing an elongated ligand-binding site that extends along its membrane distal half. This contacts haptoglobin and the ß-subunit of haemoglobin, showing how the receptor selectively binds HpHb over individual components. Lateral mobility of the glycosylphosphatidylinositol-anchored HpHbR, and a â¼50° kink in the receptor, allows two receptors to simultaneously bind one HpHb dimer. Indeed, trypanosomes take up dimeric HpHb at significantly lower concentrations than monomeric HpHb, due to increased ligand avidity that comes from bivalent binding. The structure therefore reveals the molecular basis for ligand and innate immunity factor uptake by trypanosomes and identifies adaptations that allow efficient ligand uptake in the context of the complex trypanosome cell surface.