rna interference of trypanosoma brucei cathepsin b and l affects disease progression in a mouse modelrna干扰的锥虫属brucei组织蛋白酶b和l在小鼠模型中影响疾病进展.pdfVIP

RNA Interference of Trypanosoma brucei Cathepsin B and L Affects Disease Progression in a Mouse Model 1 1 1 1 2 Maha-Hamadien Abdulla *, Theresa O’Brien , Zachary B. Mackey , Mohamed Sajid , Dennis J. Grab , James H. McKerrow1 1 Sandler Center for Basic Research in Parasitic Diseases, California Institute for Quantitative Biomedical Research, University of California San Francisco, San Francisco, California, United States of America, 2 Department of Pediatrics, Division of Infectious Diseases, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America 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. Citation: Abdulla M-H, O’Brien T, Mackey ZB, Sajid M, Grab DJ, et al. (2008) RNA Interference of Trypanosoma brucei Cathepsin B and L Affects Disease Progression