Trypanosome resistance to human innate immunity: targeting Achilles' heel

Abstract

Trypanosome lytic factors (TLFs) are powerful, naturally occurring toxins in humans that provide sterile protection against infection by several African trypanosomes. These trypanocidal complexes predominantly enter the parasite by binding to the trypanosome haptoglobin/hemoglobin receptor (HpHbR), trafficking to the lysosome, causing membrane damage and, ultimately, cell lysis. Despite TLF-mediated immunity, the parasites that cause human African Trypanosomiasis (HAT), Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense, have developed independent mechanisms of resistance to TLF killing. In this review we describe the parasite defenses that allow trypanosome infections of humans and discuss how targeting these apparent strengths of the parasite may reveal their Achilles' heel, leading to new approaches in the treatment of HAT.

Figure 1

SRA-mediated inhibition of TLF. (a) Fluorescence microscopy showing uptake of Alexa 488-conjugated TLF (green). The lysosome is shown by anti-TbCatL staining (red). The nucleus and kinetoplast are shown by DAPI staining (blue). Cells are shown by DIC imaging. Colocalization is shown by the white arrowhead (26). (b) Schematic diagram depicting neutralization resistance mechanism. SRA binds TLF via apoL-I within the early endosomes. The SRA/TLF complex traffics to the lysosome where apoL-I insertion into the lysosomal membrane is prevented by SRA binding. Prevention of apoL-I insertion in turn prevents membrane association of all TLF proteins. Without membrane association, the particle is more susceptible to lysosomal proteolysis and accelerated degradation results in clearance of the toxin (black arrow indicates direction of vesicle trafficking).

Figure 2

Alignment of mutations in the trypanosome HpHbR receptor. Five mutations have been identified in several different T. b. gambiense strains (red).

Figure 3

TbgHpHbR-Mediated Inhibition of TLF. (a) Fluorescence microscopy showing uptake of Alexa 488-conjugated TLF (green) (47). Schematic diagram depicting TLF uptake in sensitive cells via TbbHpHbR. TbbHpHbR is expressed in the flagellar pocket and binds Hb-bound TLF with high affinity, allowing TLF uptake. (b) Fluorescence microscopy showing lack of uptake of Alexa 488-conjugated TLF (green) (47). Schematic diagram depicting lack of recognition resistance mechanism. TbgHbHpR is downregulated and has mutations which prevent TLF binding and endocytosis. In the fluorescent images, the lysosome is shown by lysotracker staining (red). The nucleus and kinetoplast are shown by DAPI staining (blue). Cells are depicted by phase contrast (47).