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.
The presence of four iron-containing superoxide dismutase isozymes in Trypanosomatidae : characterization, subcellular localization, and phylogenetic origin in Trypanosoma brucei Dufernez, Fabienne; Yernaux, Cedric; Gerbod, Delphine; Noel, Christophe; Chauvenet, Melanie; Wintjens, Rene; Edgcomb, Virginia P.; Capron, Monique; Opperdoes, Fred R.; Viscogliosi, Eric (2005-08-11)Metalloenzymes such as the superoxide dismutases (SODs) form part of a defense mechanism that helps protect obligate and facultative aerobic organisms from oxygen toxicity and damage. Here, we report the presence in the ...
Serum resistance-associated protein blocks lysosomal targeting of trypanosome lytic factor in Trypanosoma brucei Oli, Monika W.; Cotlin, Laura F.; Shiflett, April M.; Hajduk, Stephen L. (American Society for Microbiology, 2006-01)Trypanosoma brucei brucei is the causative agent of nagana in cattle and can infect a wide range of mammals but is unable to infect humans because it is susceptible to the innate cytotoxic activity of normal human serum. ...
Repurposing human PDE4 inhibitors for neglected tropical diseases : design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors Amata, Emanuele; Bland, Nicholas D.; Hoyt, Charles T.; Settimo, Luca; Campbell, Robert K.; Pollastri, Michael P. (2014-07)A medicinal chemistry exploration of the human phosphodiesterase 4 (hPDE4) inhibitor cilomilast (1) was undertaken in order to identify inhibitors of phosphodiesterase B1 of Trypanosoma brucei (TbrPDEB1). T. brucei is the ...