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Liposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by Mycobacterium tuberculosis and Helps Control the Phagosomal Replicative Niches

2023-01-06Journal article Open access
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dc.contributor.authorPires, David
dc.contributor.authorMandal, Manoj
dc.contributor.authorPinho, Jacinta O.
dc.contributor.authorCatalão, Maria João
dc.contributor.authorAlmeida, António J.
dc.contributor.authorAzevedo-Pereira, J. M.
dc.contributor.authorGaspar, Maria Manuela
dc.contributor.authorAnes, Elsa
dc.date.accessioned2023-08-18T11:47:17Z
dc.date.available2023-08-18T11:47:17Z
dc.date.issued2023-01-06
dc.date.updated2023-01-10T14:36:31Z
dc.description.abstractMycobacterium tuberculosis 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.pt_PT
dc.description.sponsorshipThis research was funded by Fundação para a Ciência e a Tecnologia (FCT), grant numbers PTDC/SAU-INF/28182/2017 to EA, EXPL/SAU-INF/0742/2021 to DP, UIDB/04138/2020 to IMed-ULisboa. MM is supported by a PhD fellowship from FCT with the reference 2021.07978.BD.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationPires D, Mandal M, Pinho J, Catalão MJ, Almeida AJ, Azevedo-Pereira JM, et al. Liposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by Mycobacterium tuberculosis and Helps Control the Phagosomal Replicative Niches. International Journal of Molecular Sciences [Internet]. 2023 Jan 6;24(2):1142. Available from: http://dx.doi.org/10.3390/ijms24021142pt_PT
dc.identifier.doi10.3390/ijms24021142pt_PT
dc.identifier.slugcv-prod-3112515
dc.identifier.urihttp://hdl.handle.net/10451/58923
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationDevelopment and validation of a 3D cell culture model of the tuberculosis granuloma that can be applied for drug discovery and host cellular studies in the context of a latent infection and multicellular immunologic response.
dc.relationResearch Institute for Medicines
dc.relationDeveloping host-directed-therapies for Mycobacterium tuberculosis infection and HIV co-infection based on Cystatins manipulation
dc.relation.publisherversionhttps://www.mdpi.com/1422-0067/24/2/1142pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjecttuberculosispt_PT
dc.subjectphagosomal nichespt_PT
dc.subjectsurvival strategiespt_PT
dc.subjectcathepsinspt_PT
dc.subjectsaquinavirpt_PT
dc.subjectprotease inhibitorspt_PT
dc.subjectliposomespt_PT
dc.subjecthost directed therapiespt_PT
dc.titleLiposomal Delivery of Saquinavir to Macrophages Overcomes Cathepsin Blockade by Mycobacterium tuberculosis and Helps Control the Phagosomal Replicative Nichespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleDevelopment and validation of a 3D cell culture model of the tuberculosis granuloma that can be applied for drug discovery and host cellular studies in the context of a latent infection and multicellular immunologic response.
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleDeveloping host-directed-therapies for Mycobacterium tuberculosis infection and HIV co-infection based on Cystatins manipulation
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-INF%2F28182%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/EXPL%2FSAU-INF%2F0742%2F2021/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//2021.07978.BD/PT
oaire.citation.issue2pt_PT
oaire.citation.startPage1142pt_PT
oaire.citation.titleInternational Journal of Molecular Sciencespt_PT
oaire.citation.volume24pt_PT
oaire.fundingStream3599-PPCDT
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oaire.fundingStream6817 - DCRRNI ID
person.familyNameRODRIGUES PIRES
person.familyNameMandal
person.familyNameO. Pinho
person.familyNameGracias Fernandes da Costa Catalão
person.familyNameLeitão das Neves Almeida
person.familyNameAzevedo Pereira
person.familyNamede Jesus Guilherme Gaspar
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person.givenNameDAVID ALEXANDRE
person.givenNameManoj Kumar
person.givenNameJacinta
person.givenNameMaria João
person.givenNameAntónio José
person.givenNameJosé Miguel
person.givenNameMaria Manuela
person.givenNameELSA MARIA
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project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.nameFundação para a Ciência e a Tecnologia
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rcaap.cv.cienciaid1A10-7DAD-D860 | ELSA MARIA RIBEIRO DOS SANTOS ANES
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rcaap.typearticlept_PT
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