title: The plasma membrane of bloodstream-form African trypanosomes confers susceptibility and specificity to killing by hydrophobic peptides.
abstract: Trypanosoma brucei is the causative agent of both a veterinary wasting disease and human African trypanosomiasis, or sleeping sickness. The cell membrane of the developmental stage found within the mammalian host, the bloodstream form (BSF), is highly dynamic, exhibiting rapid rates of endocytosis and lateral flow of glycosylphosphatidylinositol-anchored proteins. Here, we show that the cell membrane of these organisms is a target for killing by small hydrophobic peptides that increase the rigidity of lipid bilayers. Specifically, we have derived trypanocidal peptides that are based upon the hydrophobic N-terminal signal sequences of human apolipoproteins. These peptides selectively partitioned into the plasma membrane of BSF trypanosomes, resulting in an increase in the rigidity of the bilayer, dramatic changes in cell motility, and subsequent cell death. No killing of the developmental stage found within the insect midgut, the procyclic form, was observed. Additionally, the peptides exhibited no toxicity toward mammalian cell lines and did not induce hemolysis. Studies with model liposomes indicated that bilayer fluidity dictates the susceptibility of membranes to manipulation by hydrophobic peptides. We suggest that the composition of the BSF trypanosome cell membrane confers a high degree of fluidity and unique susceptibility to killing by hydrophobic peptides and is therefore a target for the development of trypanocidal drugs.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia 30602, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Harrington
authors.forename: Justin
authors.initials: J
authors.lastname: Widener
authors.forename: Natalie
authors.initials: N
authors.lastname: Stephens
authors.forename: Thomas
authors.initials: T
authors.lastname: Johnson
authors.forename: Maria
authors.initials: M
authors.lastname: Francia
authors.forename: Paul
authors.initials: P
authors.lastname: Capewell
authors.forename: Annette
authors.initials: A
authors.lastname: Macleod
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hajduk
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D001053:Apolipoproteins / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008081:Liposomes / Q000494:pharmacology; D008560:Membrane Fluidity / Q000187:drug effects*; D021382:Protein Sorting Signals; D014346:Trypanosoma brucei brucei / Q000378:metabolism*; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D001053:Apolipoproteins; D008081:Liposomes; D021382:Protein Sorting Signals