RNA interference of Trypanosoma brucei cathepsin B and L affects disease progression in a mouse model.
- Author(s): Abdulla, Maha-Hamadien
- O'Brien, Theresa
- Mackey, Zachary B
- Sajid, Mohamed
- Grab, Dennis J
- McKerrow, James H
- et al.
Published Web Locationhttps://doi.org/10.1371/journal.pntd.0000298
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.