RNA interference of Trypanosoma brucei cathepsin B and L affects disease progression in a mouse model.
We investigated the roles played by the cysteine proteases cathepsin B and cathepsin L (brucipain) in the pathogenesis of Trypansoma brucei brucei in both an in vivo mouse model and an in vitro model of the blood-brain barrier. Doxycycline induction of RNAi targeting cathepsin B led to parasite clearance from the bloodstream and prevent a lethal infection in the mice. In contrast, all mice infected with T. brucei containing the uninduced Trypanosoma brucei cathepsin B (TbCatB) RNA construct died by day 13. Induction of RNAi against brucipain did not cure mice from infection; however, 50% of these mice survived 60 days longer than uninduced controls. The ability of T. b. brucei to cross an in vitro model of the human blood-brain barrier was also reduced by brucipain RNAi induction. Taken together, the data suggest that while TbCatB is the more likely target for the development of new chemotherapy, a possible role for brucipain is in facilitating parasite entry into the brain.
Abdulla
Maha-Hamadien
MH
Sandler Center for Basic Research in Parasitic Diseases, California Institute for Quantitative Biomedical Research, University of California San Francisco, San Francisco, California, USA. maha.abdulla@ucsf.edu
O'Brien
Theresa
T
Mackey
Zachary B
ZB
Sajid
Mohamed
M
Grab
Dennis J
DJ
McKerrow
James H
JH
D000818:Animals; D002401:Cathepsin B / Q000235:genetics*; D056668:Cathepsin L / Q000235:genetics*; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D008018:Life Cycle Stages / Q000235:genetics / Q000502:physiology; D051379:Mice; D023421:Models, Animal; D010957:Plasmids; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013752:Tetracycline / Q000494:pharmacology; D014162:Transfection; D014346:Trypanosoma brucei brucei / Q000201:enzymology* / Q000235:genetics* / Q000502:physiology; D014353:Trypanosomiasis, African
D015800:Protozoan Proteins; D003546:Cysteine Endopeptidases; C100684:trypanopain Tb; D002401:Cathepsin B; D056668:Cathepsin L; D013752:Tetracycline