A Single Amino Acid Substitution in the Group 1 Trypanosoma brucei gambiense Haptoglobin-Hemoglobin Receptor Abolishes TLF-1 Binding

Critical to human innate immunity against african trypanosomes is a minor subclass of human high-density lipoproteins,termed trypanosome lytic factor-1 (tlf-1). this primate-specific molecule binds to a haptoglobin-hemoglobin receptor (hphbr) on the surface of susceptible trypanosomes,initiating a lytic pathway. group 1 trypanosoma brucei gambiense causes human african trypanosomiasis (hat),escaping tlf-1 killing due to reduced uptake. previously,we found that group 1 t. b. gambiense hphbr (tbghphbr) mrna levels were greatly reduced and the gene contained substitutions within the open reading frame. here we show that a single,highly conserved amino acid in the tbghphbr ablates high affinity tlf-1 binding and subsequent endocytosis,thus evading tlf-1 killing. in addition,we show that over-expression of tbghphbr failed to rescue tlf-1 susceptibility. these findings suggest that the single substitution present in the tbghphbr directly contributes to the reduced uptake and resistance to tlf-1 seen in these important human pathogens. © 2013 dejesus et al.