title: RNA interference of Trypanosoma brucei cathepsin B and L affects disease progression in a mouse model.
abstract: 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.
authors.affiliation: 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
authors.forename: Maha-Hamadien
authors.initials: MH
authors.lastname: Abdulla
authors.forename: Theresa
authors.initials: T
authors.lastname: O'Brien
authors.forename: Zachary B
authors.initials: ZB
authors.lastname: Mackey
authors.forename: Mohamed
authors.initials: M
authors.lastname: Sajid
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Grab
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
mesh_terms: 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
chemical_list: D015800:Protozoan Proteins; D003546:Cysteine Endopeptidases; C100684:trypanopain Tb; D002401:Cathepsin B; D056668:Cathepsin L; D013752:Tetracycline