Trypanosome lytic factor (TLF-1) is an unusual high density lipoprotein (HD
L) found inhuman serum that is toxic to Trypanosoma brucei bruce! and may b
e critical in preventing human infections by this parasite. TLF-1 is compos
ed of four major apolipoproteins: apolipoprotein AI, apolipoprotein AII, pa
raoxonase, and the primate-specific haptoglobin-related protein (Hpr). Hpr
is greater than 90% homologous to haptoglobin (Hp), an abundant acute phase
serum protein. Killing of trypanosomes by TLF-1 requires cell sin-face bin
ding, endocytosis, and subsequent lysosomal targeting. Low temperature bind
ing studies reveal two receptors for TLF-1: one that is high affinity/low c
apacity (K-d similar to 12 nM, 350 receptors per cell) and another that bin
ds with low affinity/ high capacity (K-d similar to 1 muM, 60,000 receptors
per cell). The low affinity binding is competed by nonlytic human HDL and
is likely to be apolipoprotein Al-mediated. Purified human Hpr and human Hp
bind to trypanosomes, are internalized, and are targeted to the lysosome.
Furthermore,. Hpr shows competition for TLF-1 binding, and a monoclonal ant
ibody against Hpr prevents both TLF-1 uptake and trypanosome killing. Based
on these results, we propose that Hpr mediates the high affinity binding o
f TLF-1 to T. b. brucei through a haptoglobin-like receptor.