title: Mutual self-defence: the trypanolytic factor story.
abstract: Around 1900 Laveran and Mesnil discovered that African trypanosomes (prototype: Trypanosoma brucei brucei) do not survive in the blood of some primates and humans. The nature of the trypanolytic factor present in these sera has been the focus of a long-standing debate between different groups, but recent developments have allowed the proposal of a coherent model incorporating most seemingly divergent views and providing an interesting example of the complex interplay that continuously occurs between hosts and parasites. Possibly as an adaptation to their natural environment, great African apes and humans have acquired a new member of the apolipoprotein-L family, termed apoL1. This protein is the only one of the family to be secreted in the blood, where it binds to a subset of HDL particles that also contain another human-specific protein, haptoglobin-related protein or Hpr. T. b. brucei possesses a specific surface receptor for the haptoglobin-hemoglobin (Hp-Hb) complex, as a way to capture heme into hemoproteins that contribute to cell growth and resistance to the oxidative stress of the host. As this receptor does not discriminate between Hp and Hpr, Hpr-containing HDL particles of human serum are efficiently taken up by the parasite, leading to the simultaneous internalization of apoL1, Hpr and Hb-derived heme. Once in the lysosome, apoL1 is targeted to the lysosomal membrane, where its colicin-like anionic pore-forming activity triggers an influx of chloride ions from the cytoplasm. Osmotic effect linked to this ionic flux leads to uncontrolled swelling of the lysosome, ultimately causing the death of the parasite. Two T. brucei clones, termed Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, have managed to resist this lysis mechanism and, therefore, cause sleeping sickness in humans. While the mechanism of this resistance is still not known in the case of T. b. gambiense, the dominant factor responsible for resistance of T. b. rhodesiense has been identified. This protein, named SRA for Serum Resistance-Associated, is a truncated version of the major and variable surface antigen of the parasite, the Variant Surface Glycoprotein or VSG. Presumably due to its defective nature, SRA is not targeted to the plasma membrane as do regular VSGs, but ends up in the late endosomal compartment. In this location SRA is thought to neutralize apoL1 through coiled-coil interactions between alpha-helices. We discuss the potential of these discoveries in terms of fight against the disease.
authors.affiliation: Laboratory of Molecular Parasitology, Université Libre de Bruxelles, Gosselies, Belgium. epays@ulb.ac.be
authors.forename: Etienne
authors.initials: E
authors.lastname: Pays
authors.forename: Benoit
authors.initials: B
authors.lastname: Vanhollebeke
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology / Q000502:physiology*; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000276:immunology / Q000502:physiology*; D006242:Haptoglobins / Q000276:immunology / Q000502:physiology*; D006790:Host-Parasite Interactions; D006801:Humans; D007113:Immunity, Innate; D008075:Lipoproteins, HDL / Q000097:blood / Q000737:chemistry* / Q000276:immunology / Q000502:physiology*; D053440:Lipoproteins, HDL3 / Q000276:immunology / Q000502:physiology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology*; D008954:Models, Biological; D015800:Protozoan Proteins / Q000276:immunology / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000276:immunology / Q000502:physiology; D014346:Trypanosoma brucei brucei / Q000276:immunology* / Q000502:physiology*; D014347:Trypanosoma brucei gambiense / Q000276:immunology / Q000502:physiology; D016833:Trypanosoma brucei rhodesiense / Q000276:immunology / Q000502:physiology; D014353:Trypanosomiasis, African / Q000276:immunology* / Q000469:parasitology
chemical_list: C108666:APOL1 protein, human; D000951:Antigens, Neoplasm; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; C058632:HPR protein, human; D006242:Haptoglobins; D008075:Lipoproteins, HDL; D053440:Lipoproteins, HDL3; D008562:Membrane Glycoproteins; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; C434063:TLF1 protein, human; C027079:hemoglobin-haptoglobin receptor; C403774:serum resistance associated protein, Trypanosoma brucei