In vitro generation of human high-density-lipoprotein-resistant Trypanosoma brucei brucei
Faulkner, Sara D.
Oli, Monika W.
Cotlin, Laura F.
Shiflett, April M.
Cipriano, Michael J.
Pacocha, Sarah E.
Birkeland, Shanda R.
Hajduk, Stephen L.
McArthur, Andrew G.
MetadataShow full item record
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.
Author Posting. © American Society for Microbiology, 2006. This article is posted here by permission of American Society for Microbiology for personal use, not for redistribution. The definitive version was published in Eukaryotic Cell 5 (2006): 1276-1286, doi:10.1128/EC.00116-06.
Showing items related by title, author, creator and subject.
Evaluation of pyrrolidine and pyrazolone derivatives as inhibitors of trypanosomal phosphodiesterase B1 (TbrPDEB1) Amata, Emanuele; Bland, Nicholas D.; Campbell, Robert K.; Pollastri, Michael P. (2015-04-13)Human African trypanosomiasis (HAT) is a parasitic disease, caused by the protozoan pathogen Trypanosoma brucei, which affects thousands every year and which is in need of new therapeutics. Herein we report the synthesis ...
Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. 1. Sildenafil analogs Wang, Cuihua; Ashton, Trent D.; Gustafson, Alden; Bland, Nicholas D.; Ochiana, Stefan O.; Campbell, Robert K.; Pollastri, Michael P. (2012-01)Parasitic diseases, such as African sleeping sickness, have a significant impact on the health and well-being in the poorest regions of the world. Pragmatic drug discovery efforts are needed to find new therapeutic agents. ...
Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. 2. Tadalafil analogs Ochiana, Stefan O.; Gustafson, Alden; Bland, Nicholas D.; Wang, Cuihua; Russo, Michael J.; Campbell, Robert K.; Pollastri, Michael P. (2012-02-02)In this report we describe our ongoing target repurposing efforts focused on discovery of inhibitors of the essential trypanosomal phosphodiesterase TbrPDEB1. This enzyme has been implicated in virulence of Trypanosoma ...