Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor
- 30 August 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 107 (37), 16137-16141
- https://doi.org/10.1073/pnas.1007074107
Abstract
Human innate immunity against most African trypanosomes, including Trypanosoma brucei brucei, is mediated by a minor subclass of toxic serum HDL, called trypanosome lytic factor-1 (TLF-1). This HDL contains two primate specific proteins, apolipoprotein L-1 and haptoglobin (Hp)-related protein, as well as apolipoprotein A-1. These assembled proteins provide a powerful defense against trypanosome infection. Trypanosoma brucei rhodesiense causes human African sleeping sickness because it has evolved an inhibitor of TLF-1, serum resistance-associated (SRA) protein. Trypanosoma brucei gambiense lacks the SRA gene, yet it infects humans. As transfection of T. b. gambiense (group 1) is not possible, we initially used in vitro-selected TLF-1-resistant T. b. brucei to examine SRA-independent mechanisms of TLF-1 resistance. Here we show that TLF-1 resistance in T. b. brucei is caused by reduced expression of the Hp/Hb receptor gene (TbbHpHbR). Importantly, T. b. gambiense (group 1) also showed a marked reduction in uptake of TLF-1 and a corresponding decrease in expression of T. b. gambiense Hp/Hb receptor (TbgHpHbR). Ectopic expression of TbbHpHbR in TLF-1-resistant T. b. brucei rescued TLF-1 uptake, demonstrating that decreased TbbHpHbR expression conferred TLF-1 resistance. Ectopic expression of TbgHpHbR in TLF-1-resistant T. b. brucei failed to rescue TLF-1 killing, suggesting that coding sequence changes altered Hp/Hb receptor binding affinity for TLF-1. We propose that the combination of coding sequence mutations and decreased expression of TbgHpHbR directly contribute to parasite evasion of human innate immunity and infectivity of group 1 T. b. gambiense.Keywords
This publication has 31 references indexed in Scilit:
- C-Terminal Mutants of Apolipoprotein L-I Efficiently Kill Both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiensePLoS Pathogens, 2009
- Membrane Permeabilization by Trypanosome Lytic Factor, a Cytolytic Human High Density LipoproteinJournal of Biological Chemistry, 2009
- Apolipoprotein L1, a Novel Bcl-2 Homology Domain 3-only Lipid-binding Protein, Induces Autophagic Cell DeathJournal of Biological Chemistry, 2008
- Distinct roles of apolipoprotein components within the trypanosome lytic factor complex revealed in a novel transgenic mouse modelThe Journal of Experimental Medicine, 2008
- Hemoglobin Is a Co-Factor of Human Trypanosome Lytic FactorPLoS Pathogens, 2007
- Haptoglobin-related protein is a high-affinity hemoglobin-binding plasma proteinBlood, 2006
- In Vitro Generation of Human High-Density-Lipoprotein-Resistant Trypanosoma brucei bruceiEukaryotic Cell, 2006
- Trypanosome lytic factor, a subclass of high-density lipoprotein, forms cation-selective pores in membranesMolecular and Biochemical Parasitology, 2005
- Apolipoprotein L-I is the trypanosome lytic factor of human serumNature, 2003
- Will the real Trypanosoma b. gambiense please stand upParasitology Today, 1986