Mechanism of Trypanosoma brucei gambiense (group 1) resistance to human trypanosome lytic factor.
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.
Kieft
Rudo
R
Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA.
Capewell
Paul
P
Turner
C Michael R
CM
Veitch
Nicola J
NJ
MacLeod
Annette
A
Hajduk
Stephen
S
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014347:Trypanosoma brucei gambiense / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism*
D008075:Lipoproteins, HDL; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C434063:TLF1 protein, human; C027079:hemoglobin-haptoglobin receptor
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