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The molecular arms race between African trypanosomes and humans

Key Points

  • Humans resist the African trypanosome Trypanosoma brucei owing to the trypanolytic activity of the primate-specific protein apolipoprotein L1 (APOL1). APOL1 is associated with two different serum complexes, which are known as trypanosome lytic factor 1 (TLF1) and TLF2.

  • TLF1 uptake in the parasite is mediated by the surface receptor that is normally used to internalize the haptoglobin–haemoglobin complex for recovery of haem; high haptoglobin–haemoglobin levels can inhibit TLF1 uptake via receptor saturation. The mechanism of TLF2 uptake is not known, but it is not inhibited by haptoglobin–haemoglobin.

  • APOL1 kills trypanosomes following pH-dependent anionic-pore formation in the endocytic system, which disrupts ionic homeostasis.

  • Two T. brucei subspecies, T. b. rhodesiense and T. b. gambiense, can resist APOL1 toxicity and are thus able to infect humans, causing sleeping sickness.

  • The factors that enable T. b. rhodesiense and T. b. gambiense to resist APOL1, which are respectively known as serum resistance-associated (SRA) protein and T. b. gambiense-specific glycoprotein (TgsGP), are both derived from the variable surface glycoprotein (VSG) antigen of the parasite. Although SRA inhibits APOL1 following direct interaction with the toxin, TgsGP prevents APOL1 toxicity in a process that is associated with membrane lipid stiffening, which cannot protect the parasite against high APOL1 intake.

  • Full resistance of T. b. gambiense to APOL1 involves increased APOL1 digestion and mutation-mediated inactivation of the haptoglobin–haemoglobin receptor to prevent massive TLF1 uptake. This is relevant to the field situation, as in western and central Africa, the frequency of hypohaptoglobinaemia, which favours TLF1 uptake, is high owing to malaria.

  • Some APOL1 variants can escape neutralization by SRA and can thus kill T. b. rhodesiense. Such variants, which are known as G1 and G2, are frequent in western and central Africa, which could explain the elimination of T. b. rhodesiense from this part of the continent. However, these mutations are linked to a high probability of developing kidney sclerosis.

  • The APOL family shares structural and functional similarities with the apoptotic BCL2 family. APOL1 variants could induce kidney sclerosis by interfering with the control of autophagy and death programming in podocytes.

  • Humans are protected against infection by some species of African trypanosomes, owing to the presence of trypanosome-specific serum complexes. The two trypanosome subspecies that are responsible for human sleeping sickness, which are T. b. rhodesiense and T. b. gambiense, can evade this defence mechanism. Pays et al. review the mechanisms that are involved in the serum-mediated killing of trypanosomes and its evasion.

Abstract

Humans can survive bloodstream infection by African trypanosomes, owing to the activity of serum complexes that have efficient trypanosome-killing ability. The two trypanosome subspecies that are responsible for human sleeping sickness — Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense — can evade this defence mechanism by expressing distinct resistance proteins. In turn, sequence variation in the gene that encodes the trypanosome-killing component in human serum has enabled populations in western Africa to restore resistance to T. b. rhodesiense, at the expense of the high probability of developing kidney sclerosis. These findings highlight the importance of resistance to trypanosomes in human evolution.

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Figure 1: Models for the uptake and intracellular trafficking of TLF1 and TLF2 in Trypanosoma brucei brucei.
Figure 2: Schematic structure of APOL1.
Figure 3: Differential APOL1 trafficking in the three Trypanosoma bruce subspecies.
Figure 4: VSG-derived adaptive proteins in human-infective Trypanosoma bruce subspecies.
Figure 5: Downregulation of TLF1 uptake in Trypanosoma brucei gambiense.
Figure 6: Molecular 'arms race' between African trypanosomes and humans.

References

  1. Simarro, P. P., Diarra, A., Ruiz Postigo, J. A., Franco, J. R. & Jannin, J. G. The human African trypanosomiasis control and surveillance programme of the World Health Organization 2000–2009: the way forward. PLoS Negl. Trop. Dis. 5, e1007 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  2. MacGregor, P., Szöőr, B., Savill, N. J. & Matthews, K. R. Trypanosomal immune evasion, chronicity and transmission: an elegant balancing act. Nature Rev. Microbiol. 10, 431–438 (2012).

    Article  CAS  Google Scholar 

  3. Simarro, P. P. et al. The Atlas of human African trypanosomiasis: a contribution to global mapping of neglected tropical diseases. Int. J. Health Geogr. 9, 57 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hajduk, S. L. et al. Lysis of Trypanosoma brucei by a toxic subspecies of human high density lipoprotein. J. Biol. Chem. 264, 5210–5217 (1989).

    CAS  PubMed  Google Scholar 

  5. Raper, J., Fung, R., Ghiso, J., Nussenzweig, V. & Tomlinson, S. Characterization of a novel trypanosome lytic factor from human serum. Infect. Immun. 67, 1910–1916 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Pays, E. et al. The trypanolytic factor of human serum. Nature Rev. Microbiol. 4, 477–486 (2006).

    Article  CAS  Google Scholar 

  7. Drain, J., Bishop, J. R. & Hajduk, S. L. Haptoglobin-related protein mediates trypanosome lytic factor binding to trypanosomes. J. Biol. Chem. 276, 30254–30260 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Vanhollebeke, B. et al. Distinct roles of haptoglobin-related protein and apolipoprotein L-I in trypanolysis by human serum. Proc. Natl Acad. Sci. USA 104, 4118–4123 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Molina-Portela, M. P., Samanovic, M. & Raper, J. Distinct roles of apolipoprotein components within the trypanosome lytic factor complex revealed in a novel transgenic mouse model. J. Exp. Med. 205, 1721–1728 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mikkelsen, T. S. et al. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005).

    Article  CAS  Google Scholar 

  11. Maeda, N. Nucleotide sequence of the haptoglobin and haptoglobin-related gene pair. The haptoglobin-related gene contains a retrovirus-like element. J. Biol. Chem. 260, 6698–6709 (1985).

    CAS  PubMed  Google Scholar 

  12. Widener, J., Nielsen, M. J., Shiflett, A., Moestrup, S. K. & Hajduk, S. Haemoglobin is a co-factor of human trypanosome lytic factor. PLoS Pathog. 3, 1250–1261 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Vanhollebeke, B. et al. A haptoglobin–haemoglobin receptor conveys innate immunity to Trypanosoma brucei in humans. Science 320, 677–681 (2008). This study identifies the parasite surface receptor for both haptoglobin–haemoglobin and TLF1 and provides the first evidence for haem-mediated function in bloodstream form trypanosomes: resistance to oxidative stress from macrophages.

    Article  CAS  PubMed  Google Scholar 

  14. Vanhollebeke, B. & Pays, E. The trypanolytic factor of human serum: many ways to enter the parasite, a single way to kill. Mol. Microbiol. 76, 806–814 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Smith, A. B., Esko, J. D. & Hajduk, S. L. Killing of trypanosomes by the human haptoglobin-related protein. Science 268, 284–286 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Harrington, J. M., Howell, S. & Hajduk, S. L. Membrane permeabilization by trypanosome lytic factor, a cytolytic human high density lipoprotein. J. Biol. Chem. 284, 13505–13512 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Harrington, J. M. et al. The plasma membrane of bloodstream-form African trypanosomes confers susceptibility and specificity to killing by hydrophobic peptides. J. Biol. Chem. 285, 28659–28666 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Molina-Portela Mdel, P., Raper, J. & Tomlinson, S. An investigation into the mechanism of trypanosome lysis by human factors. Mol. Biochem. Parasitol. 110, 273–282 (2000).

    Article  Google Scholar 

  19. Vanhollebeke, B. et al. Human Trypanosoma evansi infection linked to a lack of apolipoprotein L-I. New Engl. J. Med. 355, 2752–2756 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Hatada, S. et al. No trypanosome lytic activity in the sera of mice producing human haptoglobin-related protein. Mol. Biochem. Parasitol. 119, 291–294 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Bullard, W. et al. Haptoglobin–hemoglobin receptor independent killing of African trypanosomes by human serum and trypanosome lytic factors. Virulence 3, 72–76 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Raper, J., Nussenzweig, V. & Tomlinson, S. Lack of correlation between haptoglobin concentration and trypanolytic activity of normal human serum. Mol. Biochem. Parasitol. 76, 337–338 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Binder, C. J. Naturally occurring IgM antibodies to oxidation-specific epitopes. Adv. Exp. Med. Biol. 750, 2–13 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Gerencer, M., Barrett, P. N., Kistner, O., Mitterer, A. & Dorner, F. Natural IgM antibodies in baby rabbit serum bind high-mannose glycans on HIV type 1 glycoprotein 120/160 and activate classic complement pathway. AIDS Res. Hum. Retroviruses. 14, 599–605 (1998).

    Article  CAS  Google Scholar 

  25. Müller, N., Mansfield, J. M. & Seebeck, T. Trypanosome variant surface glycoproteins are recognized by self-reactive antibodies in uninfected hosts. Infect. Immun. 64, 4593–4597 (1996).

    PubMed  PubMed Central  Google Scholar 

  26. D'Hondt, J., Van Meirvenne, N., Moens, L. & Kondo, M. Ca2+ is essential cofactor of trypanocidal activity of normal human serum. Nature 282, 613–615 (1979).

    Article  CAS  PubMed  Google Scholar 

  27. Vanhamme, L. et al. Apolipoprotein L-I is the trypanosome lytic factor of human serum. Nature 422, 83–87 (2003). This paper identifies the human trypanolytic protein (APOL1) and characterizes the mechanism that enables inhibition of this protein by the T. b. rhodesiense resistance protein SRA.

    Article  CAS  PubMed  Google Scholar 

  28. Duchateau, P. N. et al. Apolipoprotein L, a new human high density lipoprotein apolipoprotein expressed by the pancreas. Identification, cloning, characterization, and plasma distribution of apolipoprotein L. J. Biol. Chem. 272, 25576–25582 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Page, N. M., Butlin, D. J., Lomthaisong, K. & Lowry, P. J. The human apolipoprotein L gene cluster: identification, classification, and sites of distribution. Genomics 74, 71–78 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Vanhollebeke, B. & Pays, E. The function of apolipoproteins L. Cell. Mol. Life Sci. 63, 1937–1944 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Pérez-Morga, D. et al. Apolipoprotein L-I promotes trypanosome lysis by forming pores in lysosomal membranes. Science 309, 469–472 (2005). This paper characterizes the mechanism of trypanosome lysis by APOL1 and provides the first analysis of the structure and activity of APOLs.

    Article  CAS  PubMed  Google Scholar 

  32. Oli, M. W., Cotlin, L. F., Shiflett, A. M. & Hajduk, S. L. Serum resistance-associated protein blocks lysosomal targeting of trypanosome lytic factor in Trypanosoma brucei. Eukaryot. Cell 5, 132–139 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Stephens, N. A. & Hajduk, S. L. Endosomal localization of the serum resistance-associated protein in African trypanosomes confers human infectivity. Eukaryot. Cell 10, 1023–1033 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Uzureau, P. et al. Mechanism of Trypanosoma gambiense resistance to human serum. Nature 501, 430–434 (2013). This study characterizes the mechanism that enables T. b. gambiense to resist normal human serum and provides an explanation for the downregulation of the TLF1 receptor in this subspecies: adaptation to hypohaptoglobinaemia.

    Article  CAS  PubMed  Google Scholar 

  35. Molina-Portela Mdel, P., Lugli, E. B., Recio-Pinto, E. & Raper, J. Trypanosome lytic factor, a subclass of high-density lipoprotein, forms cation-selective pores in membranes. Mol. Biochem. Parasitol. 144, 218–226 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Lecordier, L. et al. C-terminal mutants of apolipoprotein L-I efficiently kill both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense. PLoS Pathog. 5, e1000685 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Roy, A., Kucukural, A. & Zhang, Y. I-TASSER: a unified platform for automated protein structure and function prediction. Nature Protoc. 5, 725–738 (2010).

    Article  CAS  Google Scholar 

  38. Vanhollebeke, B., Lecordier, L., Perez-Morga, D., Amiguet-Vercher, A. & Pays, E. Human serum lyses Trypanosoma brucei by triggering uncontrolled swelling of the parasite lysosome. J. Eukaryot. Microbiol. 54, 448–451 (2007).

    Article  PubMed  Google Scholar 

  39. Shiflett, A. M. et al. African trypanosomes: intracellular trafficking of host defense molecules. J. Eukaryot. Microbiol. 54, 18–21 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Boya, P. & Kroemer, G. Lysosomal membrane permeabilization in cell death. Oncogene 27, 6434–6451 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Muranjan, M., Nussenzweig, V. & Tomlinson, S. Characterization of the human serum trypanosome toxin, haptoglobin-related protein. J. Biol. Chem. 273, 3884–3887 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Raper, J., Nussenzweig, V. & Tomlinson, S. The main lytic factor of Trypanosoma brucei brucei in normal human serum is not high density lipoprotein. J. Exp. Med. 183, 1023–1029 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Smith, A. B. & Hajduk, S. L. Identification of haptoglobin as a natural inhibitor of trypanocidal activity in human serum. Proc. Natl Acad. Sci. USA 92, 10262–10266 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Rougemont, A. et al. Hypohaptoglobinaemia as an epidemiological and clinical indicator for malaria. Results of studies in a hyperendemic region in West Africa. Lancet 2, 709–712 (1988).

    Article  CAS  PubMed  Google Scholar 

  45. Alsford, S., Currier, R. B., Guerra-Assunçao, J. A., Clark, T. G. & Horn, D. Cathepsin-L can resist lysis by human serum in Trypanosoma brucei brucei. PLoS Pathog. 10, e1004130 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cascales, E. et al. Colicin biology. Microbiol. Mol. Biol. Rev. 71, 158–229 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gibson, W. Resolution of the species problem in African trypanosomes. Int. J. Parasitol. 37, 829–838 (2007).

    Article  CAS  PubMed  Google Scholar 

  48. Xong, H. V. et al. A VSG expression site-associated gene confers resistance to human serum in Trypanosoma rhodesiense. Cell 95, 839–846 (1998). This paper identifies the gene that enables T. b. rhodesiense to resist normal human serum (SRA) and provides an explanation of the relationship between the induction of this resistance and antigenic variation.

    Article  CAS  PubMed  Google Scholar 

  49. Campillo, N. & Carrington, M. The origin of the serum resistance associated (SRA) gene and a model of the structure of the SRA polypeptide from Trypanosoma brucei rhodesiense. Mol. Biochem. Parasitol. 127, 79–84 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Vanhamme, L. et al. The Trypanosoma brucei reference strain TREU927/4 contains T. brucei rhodesiense-specific SRA sequences, but displays a distinct phenotype of relative resistance to human serum. Mol. Biochem. Parasitol. 135, 39–47 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Wang, J., Böhme, U. & Cross, G. A. Structural features affecting variant surface glycoprotein expression in Trypanosoma brucei. Mol. Biochem. Parasitol. 128, 135–145 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Berberof, M., Pérez-Morga, D. & Pays, E. A receptor-like flagellar pocket glycoprotein specific to Trypanosoma brucei gambiense. Mol. Biochem. Parasitol. 113, 127–138 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Felu, C., Pasture, J., Pays, E. & Pérez-Morga, D. Diagnosis potential of a conserved genomic rearrangement in the Trypanosoma brucei gambiense-specific TGSGP locus. Am. J. Trop. Med. Hyg. 76, 922–929 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Radwanska, M. et al. Novel primer sequences for a polymerase chain reaction-based detection of Trypanosoma brucei gambiense. Am. J. Trop. Med. Hyg. 67, 289–295 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Gibson, W., Nemetschke, L. & Ndung'u, J. Conserved sequence of the TgsGP gene in Group 1 Trypanosoma brucei gambiense. Infect. Genet. Evol. 10, 453–458 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Radwanska, M. et al. The serum resistance-associated gene as a diagnostic tool for the detection of Trypanosoma brucei rhodesiense. Am. J. Trop. Med. Hyg. 67, 684–690 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Capewell, P. et al. The TgsGP gene is essential for resistance to human serum in Trypanosoma brucei gambiense. PLoS Pathog. 9, e1003686 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kieft, R. et al. Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor. Proc. Natl Acad. Sci. USA 107, 16137–16141 (2010).

    Article  PubMed  Google Scholar 

  59. Symula, R. E. et al. Trypanosoma brucei gambiense group 1 is distinguished by a unique amino acid substitution in the HpHb receptor implicated in human serum resistance. PLoS Negl. Trop. Dis. 6, e1728 (2012).

    CAS  Google Scholar 

  60. Higgins, M. K. et al. Structure of the trypanosome haptoglobin–haemoglobin receptor and implications for nutrient uptake and innate immunity. Proc. Natl Acad. Sci. USA 110, 1905–1910 (2013).

    Article  PubMed  Google Scholar 

  61. Dejesus, E., Kieft, R., Albright, B., Stephens, N. A. & Hajduk, S. L. A single amino acid substitution in the group 1 Trypanosoma brucei gambiense haptoglobin–haemoglobin receptor abolishes TLF-1 binding. PLoS Pathog. e1003317 (2013).

  62. Piel, F. B. et al. Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. Nature Commun. 1, 104 (2010).

    Article  CAS  Google Scholar 

  63. Cyrklaff, M. et al. Hemoglobins S and C interfere with actin remodeling in Plasmodium falciparum-infected erythrocytes. Science 334, 1283–1286 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Salmon, D. et al. Characterization of the ligand-binding site of the transferrin receptor in Trypanosoma brucei demonstrates a structural relationship with the N-terminal domain of the variant surface glycoprotein. EMBO J. 16, 7272–7278 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Pays, E., Lips, S., Nolan, D. P., Vanhamme, L. & Pérez-Morga, D. The VSG expression sites of Trypanosoma brucei: multipurpose tools for the adaptation of the parasite to mammalian hosts. Mol. Biochem. Parasitol. 114, 1–16 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Thomson, R., Molina-Portela, P., Mott, H., Carrington, M. & Raper, J. Hydrodynamic gene delivery of baboon trypanosome lytic factor eliminates both animal and human-infective African trypanosomes. Proc. Natl Acad. Sci. USA 106, 19509–19514 (2009). This study characterizes baboon APOL1, which confers resistance to T. b. rhodesiense.

    Article  PubMed  Google Scholar 

  67. Genovese, G. et al. Association of trypanolytic apoL1 variants with kidney disease in African-Americans. Science 329, 841–845 (2010). This paper shows that natural human APOL1 variants provide resistance to T. b. rhodesiense and provides evidence for the association of these variants with kidney disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Thomson, R. et al. Evolution of the primate trypanolytic factor APOL1. Proc. Natl Acad. Sci. USA 111, E2130–E2139 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. Kopp, J. B. et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. J. Am. Soc. Nephrol. 22, 2129–2137 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Foster, M. C. et al. APOL1 variants associate with increased risk of CKD among African Americans. J. Am. Soc. Nephrol. 24, 1484–1491 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Genovese, G., Friedman, D. J. & Pollak, M. R. APOL1 variants and kidney disease in people of recent African ancestry. Nature Rev. Nephrol. 9, 240–244 (2013).

    Article  CAS  Google Scholar 

  72. Johnstone, D. B. et al. APOL1 null alleles from a rural village in India do not correlate with glomerulosclerosis. PLoS ONE 7, e51546 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Freedman, B. I. et al. Apolipoprotein L1 nephropathy risk variants associate with HDL subfraction concentration in African Americans. Nephrol. Dial. Transplant. 26, 3805–3810 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wan, G. et al. Apolipoprotein L1, a novel Bcl-2 homology domain 3-only lipid-binding protein, induces autophagic cell death. J. Biol. Chem. 283, 21540–21549 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Zhaorigetu, S., Yang, Z., Toma, I., McCaffrey, T. A. & Hu, C. A. Apolipoprotein L6, induced in atherosclerotic lesions, promotes apoptosis and blocks Beclin1-dependent autophagy in atherosclerotic cells. J. Biol. Chem. 286, 27389–27398 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Liao, W. et al. A novel anti-apoptotic role for apolipoprotein L2 in IFN-γ-induced cytotoxicity in human bronchial epithelial cells. J. Cell. Physiol. 226, 397–406 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Smith, E. E. & Malik, H. S. The apolipoprotein L family of programmed cell death and immunity genes rapidly evolved in primates at discrete sites of host–pathogen interactions. Genome Res. 19, 850–858 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Taylor, H. E., Khatua, A. K. & Popik, W. The innate immune factor apolipoprotein L1 (APOL1) restricts HIV-1 infection. J. Virol. 88, 592–603 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hartleben, B. et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J. Clin. Invest. 120, 1084–1096 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Ko, W. Y. et al. Identifying Darwinian selection acting on different human APOL1 variants among diverse African populations. Am. J. Hum. Genet. 93, 54–66 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kageruka, P. et al. Infectivity of Trypanosoma (Trypanozoon) brucei gambiense for baboons (Papio hamadryas, Papio papio). Ann. Soc. Belg. Med. Trop. 71, 39–46 (1991).

    CAS  PubMed  Google Scholar 

  82. Willyard, C. Putting sleeping sickness to bed. Nature Med. 17, 14–17 (2011).

    Article  CAS  PubMed  Google Scholar 

  83. Salmon, D. et al. Adenylate cyclases of Trypanosoma brucei inhibit the innate immune response of the host. Science 337, 463–466 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Bosschaerts, T., Guilliams, M., Stijlemans, B., De Baetselier, P. & Beschin, A. Understanding the role of monocytic cells in liver inflammation using parasite infection as a model. Immunobiology 214, 737–747 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Paulnock, D. M., Freeman, B. E. & Mansfield, J. M. Modulation of innate immunity by African trypanosomes. Parasitology 137, 2051–2063 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Morrison, L. J. Parasite-driven pathogenesis in Trypanosoma brucei infections. Parasite Immunol. 33, 448–455 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tabel, H., Wei, G. & Bull, H. J. Immunosuppression: cause for failures of vaccines against African Trypanosomiases. PLoS Negl. Trop. Dis. 7, e2090 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Hall, J. P., Wang, H. & Barry, J. D. Mosaic VSGs and the scale of Trypanosoma brucei antigenic variation. PLoS Pathog. 9, e1003502 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Blum, M. L. et al. A structural motif in the variant surface glycoproteins of Trypanosoma brucei. Nature 362, 603–609 (1993).

    Article  CAS  PubMed  Google Scholar 

  90. Chattopadhyay, A. et al. Structure of the C-terminal domain from Trypanosoma brucei variant surface glycoprotein MITat1.2. J. Biol. Chem. 280, 7228–7235 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Morrison, L. J., Marcello, L. & McCulloch, R. Antigenic variation in the African trypanosome: molecular mechanisms and phenotypic complexity. Cell. Microbiol. 11, 1724–1734 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Research in the authors' laboratory was supported by the Walloon WELBIO excellence programme, the Belgian Fund for Scientific Research (FNRS) and the Interuniversity Attraction Poles Programme of Belgian Science Policy.

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Correspondence to Etienne Pays.

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PowerPoint slides

Glossary

Haptoglobin

A serum protein that binds to free haemoglobin with high affinity and removes it from the circulation.

Flagellar pocket

An invagination of the trypanosome plasma membrane around the base of the flagellum. This region concentrates surface receptors and is the only site of exocytosis and endocytosis.

High-mannose glycans

Protein-bound glycans that have many mannose residues, often almost as many as in the precursor oligosaccharides before attachment to the protein.

Variant surface glycoproteins

(VSGs). The main surface antigens of African trypanosomes; they undergo continuous antigenic variation.

Colicins

Toxins that are produced and released by different strains of Escherichia coli. Some colicins kill target cells by forming ionic pores in cellular membranes.

Hypoglobinaemia

A serum condition that is characterized by low (<0.3 mg per ml) haptoglobin levels.

Anhaptoglobinaemia

An absence of haptoglobin in serum.

Expression site-associated gene

(ESAG). A gene that is associated with the variant surface glycoprotein (VSG) gene in the different telomeric sites for expression of that gene. Both ESAG and VSG genes are contained in the same polygenic transcription unit that recruits ribosomal RNA polymerase.

BCL2 family

A family of proteins that govern mitochondrial outer membrane permeabilization and can be either pro- or anti-apoptotic. BCL2 proteins can interact with each other and with other apoptosis- and autophagy-controlling proteins via a BCL-homology 3 domain.

Podocyte

A type of kidney cell that wraps around the capillaries of the glomerulus. Podocytes filter blood, holding back large molecules such as proteins, and passing through small molecules such as water, salts and sugar, as the first step in forming urine.

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Pays, E., Vanhollebeke, B., Uzureau, P. et al. The molecular arms race between African trypanosomes and humans. Nat Rev Microbiol 12, 575–584 (2014). https://doi.org/10.1038/nrmicro3298

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