Abstract
The natural immunity of humans to the cattle pathogen Trypanosoma brucei brucei, but not to the morphologically indistiguishable human pathogens T. brucei gambiense and T. brucei rhodesiense, is due to the selective killing of the parasite by normal human serum. The factor in human serum that mediates lysis of T. brucei brucei has long been attributed to a minor subclass of high density lipoprotein (HDL). Evidence indicates that the trypanolytic activity of isolated human HDL is due to peroxidase activity of an associated haptoglobin-related protein-hemoglobin complex. However, recent data suggest that the trypanolytic activity of HDL may be completely inhibited in whole human serum, and that trypanolytic activity of norman human serum is due to a second, less well-defined factor of high molecular weight. Current research aimed at understanding the mechamisms of cytotoxicity and the affected metabolic pathways may open new approaches for the development of specific drugs and vaccines against trypanosomiasis.
Similar content being viewed by others
Article PDF
References
Borst, P. 1986. Discontinuous transcription and antigenic variation in trypanosomes. Ann. Rev. Biochem. 55: 701–732.
Pays, E., Vanhamme, L., and Berberof, M. 1994. Genetic controls for the expression of surface antigens in African trypanosomes. Ann. Rev. Microbiol. 48: 25–52.
World Development Report. 1993. Investing in Health World Development Indication. The World Bank 329.
Rifkin, M.R. 1978. Identification of the trypanocidal factor in normal human serum: High density lipoprotein. Proc. Natl. Acad. Sci. USA 75: 3450–3454.
Hajduk, S.L., Moore, D.R., Vasudevacharya, J., Siqueira, H., Torri, A.F., Tytler, E.M., and Esko, J.D. 1989. Lysis of Trypanosoma brucei by a toxic subspecies of human high density lipoprotein. J. Biol. Chem. 264: 5210–5217.
Seed, J.R. and Sechelski, J.B. 1989. Nature of the trypanocidal factor in human serum. J. Parasitol. 75: 1003–1006.
Gillet, M.P.T. and Owen, J.S. 1991. Trypanosoma brucei brucei: differences in the trypanocidal activity of human plasma and its relationship to the level of high density lipoproteins. Trans. R. Soc. Trop. Med. Hyg. 85: 612–616.
Lorenz, P., James, R.W., Owen, J.S., and Betschart, B. 1994. Heterogeneity in the properties of the trypanolytic factor in normal human serum. Mol. Biochem. Parasitol. 64: 153–164.
Tomlinson, S., Jansen, A.-M., Koudinov, A., Ghiso, J.A., Choi-Miura, N., Rifkin, M.R., Ohtaki, S., and Nussenzweig, V. 1995. High-density-lipoprotein-independent killing of Trypanosoma brucei by human serum. Mol. Biochem. Parasitol. 70: 131–138.
Hajduk, S.L., Hagar, K.M., and Esko, J.D. 1994. Human high density lipoprotein killing of African trypanosomes. Ann. Rev. Microbiol. 48: 139–162.
Lorenz, P., Betschart, B., and Owen, J.S. 1995. Trypanosoma brucei brucei and high density lipoproteins: old and new thoughts on the identity and mechanism of the trypanocidal factor in human serum. Parasitol. Today 11: 348–352.
Smith, A.B., Esko, J.D., and Hajduk, S.L. 1995. Killing of trypanosomes by the human haptoglobin-related protein. Science 268: 284–286.
Barth, P. 1989. A new method for the isolation of the trypanocidal factor from normal human serum. Acta Tropica 46: 71–73.
Raper, J., Nussenzweig, V., and Tomlinson, S. 1996. The main lytic factor of Trypanosoma b. brucei in normal human serum is not high density lipoprotein. J. Exp. Med. 183: 1023–1029.
Overath, P., Chaudhri, M., Steverding, D., and Ziegelbauer, K. 1994. Invariant surface proteins in bloodstream forms of Trypanosoma brucei . Parasitol. Today 10: 53–58.
Steverding, D., Stierhof, Y.-D., Fuchs, H., Tauber, R., and Overath, P. 1995. Transferrin-binding protein complex is the receptor for transferrin uptake in Trypanosoma brucei . J. Cell Biol. 131: 1173–1182.
Coppens, I., Opperdoes, F.R., Courtoy, P.J., and Baukhuin, P. 1987. Receptor mediated endocytosis in the bloodstream form of Trypanosoma brucei . Journal of Protozoology 34: 465–473.
Hagar, K.M., Pierce, M.A., Moore, D.R., Tytler, E.M., Esko, J.D., and Hajduk, S.L. 1994. Endocytosis of a cytotoxic human high density lipoprotein results in disruption of acidic intracellular vesicles and subsequent killing of african trypanosomes. J. Cell Biol. 126: 155–167.
Lorenz, P., Barth, P.E., Rudin, W., and Betschart, B. 1994. Importance of acidic intracellular compartments in the lysis of Trypanosoma brucel brucei by normal human serum. Trans. R. Soc. Trop. Med. Hyg. 88: 487–488.
Seglen, P.O. 1983. Inhibitors of lysosomal function. Meth. Enzymol. 96: 737–764.
Bastin, P., Coppens, I., Saint-Remy, J.-M., Baudhuin, P., Opperdoes, F.R., and Courtoy, P.J. 1994. Identification of a specific epitope on the extracellular domain of the LDL-receptor of Trypanosoma brucei brucei . Mol. Biochem. Parasitol. 63: 193–202.
Coppens, I., Bastin, P., Courtoy, P.J., Baudhuin, P., and Opperdoes, F.R. 1991. A rapid method purifies a glycoprotein of Mr 145 000 as the LDL receptor of Trypanosoma brucei brucei . Biochem. Biophys. Res. Comm. 178: 185–191.
Salmon, D., Geuskens, M., Hanocq, F., Nolan, D., Ruben, L., and Pays, E. 1994. A novel heterodimeric transferrin receptor encoded by a pair of VSG expression site-associated genes in T. brucei . Cell 78: 75–86.
Ligtenberg, M.J.L., Bitter, W., Kieft, R., Steverding, D., Janssen, H., Calafat, J., and Borst, P. 1994. Reconstitution of a surface transferrin binding complex in insect form Trypanosoma brucei . EMBO J. 13: 2565–2573.
Steverding, D., Stierhof, Y.-D., Chaudhri, M., Ligtenberg, M., Schell, D., Beck-Sickinger, A.G., and Overath, P. 1994. ESAG 6 and 7 products of Trypanosoma brucei form a transferrin binding protein complex. European Journal of Cell Biology 64: 78–87.
Grab, D.J., Shaw, M.K., Wells, C.W., Verjee, V., Russo, D.C.W., Webster, P., Naessens, J., and Fish, W.R. 1993. The transferrin receptor in African try-panosomes: identification, partial characterization and subcellular localization. European Journal of Cell Biology 62: 114–126.
Gillet, M.P.T. and Owen, J.S. 1992. Characteristics of the binding of human and bovine high-density lipoproteins by bloodstream forms of the African try-panosome, Trypanosoma brucei brucei . Biochim. Biophys. Acta 1123: 239–248.
Lee, G.-S.M., Bihain, B.E., Russell, D.G., Deckelbaum, R.J., and van der Ploeg, L.H.T. 1990. Characterization of a cDNA encoding a cysteine-rich cell surface protein located in the flageller pocket of the protozoan Trypanosoma brucei . Molecular and Cellular Biology 10: 4506–4517.
Tytler, E.M., Moore, D.R., Pierce, M.A., Hagar, K.M., Esko, J.D., and Hajduk, S.L. 1994. Reconstitution of the trypanosome lytic factor. The role of lipids and apolipoproteins in the cytotoxicity of a subspecies of human high density lipoproteins. Mol. Biochem. Parasitol. In press.
Maeda, N. 1985. Nucleotide sequence of the haptoglobin and haptoglobin-related gene pair. J. Biol. Chem. 260: 6698–6709.
Pintera, J. 1971. The biochemical, genetic, and clinicopathological aspects of haptoglobin. Williams & Wilkens, Baltimore.
Kawamura, K., Kagiyama, S., Ogawa, A., and Yanase, T. 1972. Kinetics of peroxidase activity, absorption spectra and oxygen affinity of human hemoglobin-haptoglobin 1-1 complexes. Biochim. Biophys. Acta 285: 22–27.
Brickman, M.J., Cook, J.M., and Balber, A.E. 1995. Low temperature reversibly inhibits transport from tubular endosomes to a perinuclear, acidic compartment in African trypanosomes. J. Cell Sci. 108: 3611–3621.
Dwyer, D.M. 1976. Immunologic and fine structure evidence of avidly bound host serum proteins in the surface coat of a bloodstream trypanosome. Proc. Natl. Acad. Sci. USA 73: 1222–1226.
Verducci, G., Perito, S., Rossi, R., Mannarino, E., Bistoni, F., and Marconi, P. 1989. Identification of a trypanocidal factor against Trypanosoma equiperdum in normal human serum. Parasitol. 98: 401–407.
Smith, A.B. and Hajduk, S.L. 1995. Identification of haptoglobin as a natural inhibitor of trypanocidal activity in human serum. Proc. Natl. Acad. Sci. USA 92: 10262–10266.
Raper, J., Nussenzweig, V., and Tomlinson, S. 1996. Lack of correlation between haptoglobin concentration and trypanolytic activity of normal human serum. Mol. Biochem. Parasitol. 76: 337–338.
Rifkin, M.R., DeGreef, C., Jiwa, A., Landsberger, F.R., and Shapiro, S.Z. 1994. Human serum-sensitive Trypanosoma brucei rhodesiense: a comparison with serologically indentical human serum-resistant clones. Mol. Biochem. Parasitol. 66: 211–220.
Hagar, K.M. and Hajduk, S.L. 1995. Cloning and characterization of human sera reistant and sensitive strains of T. b. rhodesiense . Woods Hole, MA. abstract, 79.
Ortiz, J.C., Sechelski, J.B., and Seed, J.R. 1994. Characterization of human serum-resistant and serum sensitive clones from a single Trypanosoma brucei gambiense parental clone. J. Parasitol. 80: 550–557.
De Greet, C. and Hamers, R. 1994. The serum reistance-associated (SRA) gene of Trypanosoma brucei rhodesiense encodes a variant surface glycoprotein-like protein. Mol. Biochem. Parasitol. 68: 277–284.
Lorenz, P., Owen, J.S., and Hassall, D. 1995. Human serum resistant Trypanosoma brucei rhodesiense accumulates similar amounts of fluorescently-labelled trypanolytic HDL3 particles as human serum sensitive T. b. brucei . Mol. Biochem. Parasitol. 74: 113–118.
Ortiz-Ordonez, J.C. and Seed, J.R. 1995. The removal of trypanolytic activity from human serum by Trypanosoma brucei gambiense and its subsequent recovery in trypanosome lysates. J. Parasitol. 81: 555–558.
Fairlamb, A.H. and Cerami, A. 1992. Metabolism and function of trypanothione in the kinetoplastida. Ann. Rev. Microbiol. 46: 695–729.
Molyneux, D.H., Pentreath, V., and Doua, F. 1996. pp. 1171–1196 in Manson's tropical diseases, vol. 20. Cook, G.C. (ed.). W.B. Saunders, London.
Schweizer, J., Tait, A., and Jenni, L. 1988. The timing and frequency of hybrid formation in African trypanosomes during cyclical transmission. Parasitol. Res. 75: 98–101.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Tomlinson, S., Raper, J. The lysis of Trypanosoma brucei brucei by human serum. Nat Biotechnol 14, 717–721 (1996). https://doi.org/10.1038/nbt0696-717
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/nbt0696-717
This article is cited by
-
Biochemical and genotyping analyses of camels (Camelus dromedaries) trypanosomiasis in North Africa
Scientific Reports (2023)