title: In vitro generation of human high-density-lipoprotein-resistant Trypanosoma brucei brucei.
abstract: The host range of African trypanosomes is influenced by innate protective molecules in the blood of primates. A subfraction of human high-density lipoprotein (HDL) containing apolipoprotein A-I, apolipoprotein L-I, and haptoglobin-related protein is toxic to Trypanosoma brucei brucei but not the human sleeping sickness parasite Trypanosoma brucei rhodesiense. It is thought that T. b. rhodesiense evolved from a T. b. brucei-like ancestor and expresses a defense protein that ablates the antitrypanosomal activity of human HDL. To directly investigate this possibility, we developed an in vitro selection to generate human HDL-resistant T. b. brucei. Here we show that conversion of T. b. brucei from human HDL sensitive to resistant correlates with changes in the expression of the variant surface glycoprotein (VSG) and abolished uptake of the cytotoxic human HDLs. Complete transcriptome analysis of the HDL-susceptible and -resistant trypanosomes confirmed that VSG switching had occurred but failed to reveal the expression of other genes specifically associated with human HDL resistance, including the serum resistance-associated gene (SRA) of T. b. rhodesiense. In addition, we found that while the original active expression site was still utilized, expression of three expression site-associated genes (ESAG) was altered in the HDL-resistant trypanosomes. These findings demonstrate that resistance to human HDLs can be acquired by T. b. brucei.
authors.affiliation: Josephine Bay Paul Center, Marine Biological Laboratory, 7 MBL Street, Woods Hole, MA 02543, USA.
authors.forename: Sara D
authors.initials: SD
authors.lastname: Faulkner
authors.forename: Monika W
authors.initials: MW
authors.lastname: Oli
authors.forename: Rudo
authors.initials: R
authors.lastname: Kieft
authors.forename: Laura
authors.initials: L
authors.lastname: Cotlin
authors.forename: Justin
authors.initials: J
authors.lastname: Widener
authors.forename: April
authors.initials: A
authors.lastname: Shiflett
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cipriano
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Pacocha
authors.forename: Shanda R
authors.initials: SR
authors.lastname: Birkeland
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hajduk
authors.forename: Andrew G
authors.initials: AG
authors.lastname: McArthur
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004351:Drug Resistance / Q000235:genetics*; D006801:Humans; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D015800:Protozoan Proteins / Q000235:genetics*; D016415:Sequence Alignment; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development*; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000235:genetics / Q000378:metabolism
chemical_list: D008075:Lipoproteins, HDL; D008562:Membrane Glycoproteins; D015800:Protozoan Proteins; C434063:TLF1 protein, human; D014643:Variant Surface Glycoproteins, Trypanosoma; C403774:serum resistance associated protein, Trypanosoma brucei