Liposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by <i>Mycobacterium tuberculosis</i> and Helps Control the Phagosomal Replicative Niches
<i>Mycobacterium tuberculosis</i> is able to establish a chronic colonization of lung macrophages in a controlled replication manner, giving rise to a so-called latent infection. Conversely, when intracellular bacteria undergo actively uncontrolled replication rates, they provide the swi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/2/1142 |
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| author | David Pires Manoj Mandal Jacinta Pinho Maria João Catalão António José Almeida José Miguel Azevedo-Pereira Maria Manuela Gaspar Elsa Anes |
| author_facet | David Pires Manoj Mandal Jacinta Pinho Maria João Catalão António José Almeida José Miguel Azevedo-Pereira Maria Manuela Gaspar Elsa Anes |
| author_sort | David Pires |
| collection | DOAJ |
| description | <i>Mycobacterium tuberculosis</i> is able to establish a chronic colonization of lung macrophages in a controlled replication manner, giving rise to a so-called latent infection. Conversely, when intracellular bacteria undergo actively uncontrolled replication rates, they provide the switch for the active infection called tuberculosis to occur. Our group found that the pathogen is able to manipulate the activity of endolysosomal enzymes, cathepsins, directly at the level of gene expression or indirectly by regulating their natural inhibitors, cystatins. To provide evidence for the crucial role of cathepsin manipulation for the success of tuberculosis bacilli in their intracellular survival, we used liposomal delivery of saquinavir. This protease inhibitor was previously found to be able to increase cathepsin proteolytic activity, overcoming the pathogen induced blockade. In this study, we demonstrate that incorporation in liposomes was able to increase the efficiency of saquinavir internalization in macrophages, reducing cytotoxicity at higher concentrations. Consequently, our results show a significant impact on the intracellular killing not only to reference and clinical strains susceptible to current antibiotic therapy but also to multidrug- and extensively drug-resistant (XDR) Mtb strains. Altogether, this indicates the manipulation of cathepsins as a fine-tuning strategy used by the pathogen to survive and replicate in host cells. |
| first_indexed | 2024-03-09T12:24:39Z |
| format | Article |
| id | doaj.art-44660416d6b9439dbdca8b7fc584998f |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T12:24:39Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-44660416d6b9439dbdca8b7fc584998f2023-11-30T22:36:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01242114210.3390/ijms24021142Liposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by <i>Mycobacterium tuberculosis</i> and Helps Control the Phagosomal Replicative NichesDavid Pires0Manoj Mandal1Jacinta Pinho2Maria João Catalão3António José Almeida4José Miguel Azevedo-Pereira5Maria Manuela Gaspar6Elsa Anes7Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalHost-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalAdvanced Technologies for Drug Delivery, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalHost-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalAdvanced Technologies for Drug Delivery, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalHost-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalAdvanced Technologies for Drug Delivery, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalHost-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal<i>Mycobacterium tuberculosis</i> is able to establish a chronic colonization of lung macrophages in a controlled replication manner, giving rise to a so-called latent infection. Conversely, when intracellular bacteria undergo actively uncontrolled replication rates, they provide the switch for the active infection called tuberculosis to occur. Our group found that the pathogen is able to manipulate the activity of endolysosomal enzymes, cathepsins, directly at the level of gene expression or indirectly by regulating their natural inhibitors, cystatins. To provide evidence for the crucial role of cathepsin manipulation for the success of tuberculosis bacilli in their intracellular survival, we used liposomal delivery of saquinavir. This protease inhibitor was previously found to be able to increase cathepsin proteolytic activity, overcoming the pathogen induced blockade. In this study, we demonstrate that incorporation in liposomes was able to increase the efficiency of saquinavir internalization in macrophages, reducing cytotoxicity at higher concentrations. Consequently, our results show a significant impact on the intracellular killing not only to reference and clinical strains susceptible to current antibiotic therapy but also to multidrug- and extensively drug-resistant (XDR) Mtb strains. Altogether, this indicates the manipulation of cathepsins as a fine-tuning strategy used by the pathogen to survive and replicate in host cells.https://www.mdpi.com/1422-0067/24/2/1142tuberculosisphagosomal nichessurvival strategiescathepsinssaquinavirprotease inhibitors |
| spellingShingle | David Pires Manoj Mandal Jacinta Pinho Maria João Catalão António José Almeida José Miguel Azevedo-Pereira Maria Manuela Gaspar Elsa Anes Liposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by <i>Mycobacterium tuberculosis</i> and Helps Control the Phagosomal Replicative Niches International Journal of Molecular Sciences tuberculosis phagosomal niches survival strategies cathepsins saquinavir protease inhibitors |
| title | Liposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by <i>Mycobacterium tuberculosis</i> and Helps Control the Phagosomal Replicative Niches |
| title_full | Liposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by <i>Mycobacterium tuberculosis</i> and Helps Control the Phagosomal Replicative Niches |
| title_fullStr | Liposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by <i>Mycobacterium tuberculosis</i> and Helps Control the Phagosomal Replicative Niches |
| title_full_unstemmed | Liposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by <i>Mycobacterium tuberculosis</i> and Helps Control the Phagosomal Replicative Niches |
| title_short | Liposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by <i>Mycobacterium tuberculosis</i> and Helps Control the Phagosomal Replicative Niches |
| title_sort | liposomal delivery of saquinavir to macrophages overcomes cathepsin blockade by i mycobacterium tuberculosis i and helps control the phagosomal replicative niches |
| topic | tuberculosis phagosomal niches survival strategies cathepsins saquinavir protease inhibitors |
| url | https://www.mdpi.com/1422-0067/24/2/1142 |
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