Back to Search
Start Over
Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2010 Sep 14; Vol. 107 (37), pp. 16137-41. Date of Electronic Publication: 2010 Aug 30. - Publication Year :
- 2010
-
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.
- Subjects :
- Animals
Cell Line
Gene Expression Regulation
Humans
Protein Binding
RNA Interference
RNA, Messenger genetics
Receptors, Cell Surface genetics
Receptors, Cell Surface immunology
Trypanosoma brucei gambiense immunology
Trypanosoma brucei gambiense isolation & purification
Lipoproteins, HDL metabolism
Receptors, Cell Surface metabolism
Trypanosoma brucei gambiense metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 107
- Issue :
- 37
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 20805508
- Full Text :
- https://doi.org/10.1073/pnas.1007074107