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Advisor(s)
Abstract(s)
Mycobacterium tuberculosis (Mtb) latently infects approximately a quarter of the world’s population and 10 % of these will develop the disease tuberculosis. Mtb infects macrophages, manipulating the proteolytic mechanisms, particularly, by decreasing the expression and activity of lysosomal cathepsins. Consequently, Mtb survives and even replicates inside macrophages concomitant with poor priming of the adaptive immune response. Our group found that the protease inhibitor used in antiretroviral therapy for HIV infection, saquinavir (SQV), restores and further improves the overall activity of cathepsins in Mtb-infected macrophages and more specifcally, that of cathepsin S [1]. In this study, we tested the incorporation of SQV in liposomes to establish an improved delivery method for SQV to human monocyte-derived macrophages. Using fuorophore-tagged liposomes we demonstrated the effciency of SQV-loaded liposome internalization by human macrophages. Additionally, using a general fuorescent substrate of human cathepsins we could observe improved proteolytic activity in treated macrophages. When applying this treatment to Mtb-infected macrophages these effects resulted in better control of the infection. Furthermore, liposomal delivery of SQV reduced the cytotoxicity of the treatment and allowed the usage of higher concentrations without impacting cell viability. By using this strategy, we overcame the cathepsin activity blockade that is induced by the pathogen [2]. The results further demonstrate the effcacy of SQV-loaded liposomes to help control infections by Mtb clinical strains susceptible or resistant to the current antibiotic therapy. Our results suggest the use of liposomal delivery of SQV as a potential complementary therapy against Mtb infection. Human monocytes were isolated from buffy-coats of healthy human donors provided by the National Blood Institute (Instituto Português do Sangue e da Transplantação, IP, Lisbon, Portugal).