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Cystatin F depletion in Mycobacterium tuberculosis-infected macrophages improves cathepsin C/granzyme B-driven cytotoxic effects on HIV-infected cells during coinfection

dc.contributor.authorMandal, Manoj
dc.contributor.authorPires, David
dc.contributor.authorCalado, Marta
dc.contributor.authorAzevedo-Pereira, Jose Miguel
dc.contributor.authorAnes, Elsa
dc.date.accessioned2024-09-18T11:00:48Z
dc.date.available2024-09-18T11:00:48Z
dc.date.issued2024-08
dc.description.abstractCystatin F (CstF) is a protease inhibitor of cysteine cathepsins, including those involved in activating the perforin/granzyme cytotoxic pathways. It is targeted at the endolysosomal pathway but can also be secreted to the extracellular milieu or endocytosed by bystander cells. CstF was shown to be significantly increased in tuberculous pleurisy, and during HIV coinfection, pleural fluids display high viral loads. In human macrophages, our previous results revealed a strong upregulation of CstF in phagocytes activated by interferon γ or after infection with Mycobacterium tuberculosis (Mtb). CstF manipulation using RNA silencing led to increased proteolytic activity of lysosomal cathepsins, improving Mtb intracellular killing. In the present work, we investigate the impact of CstF depletion in macrophages during the coinfection of Mtb-infected phagocytes with lymphocytes infected with HIV. The results indicate that decreasing the CstF released by phagocytes increases the major pro-granzyme convertase cathepsin C of cytotoxic immune cells from peripheral blood-derived lymphocytes. Consequently, an observed augmentation of the granzyme B cytolytic activity leads to a significant reduction in viral replication in HIV-infected CD4+ T-lymphocytes. Ultimately, this knowledge can be crucial for developing new therapeutic approaches to control both pathogens based on manipulating CstF.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.3390/ijms25158141pt_PT
dc.identifier.eid85200972466
dc.identifier.issn1661-6596
dc.identifier.pmcPMC11311260
dc.identifier.pmid39125711
dc.identifier.urihttp://hdl.handle.net/10400.14/46579
dc.identifier.wos001287805300001
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectMtb-HIV coinfectionpt_PT
dc.subjectCathepsin Cpt_PT
dc.subjectCystatin Fpt_PT
dc.subjectCytotoxic immune cellspt_PT
dc.subjectGranzyme Bpt_PT
dc.titleCystatin F depletion in Mycobacterium tuberculosis-infected macrophages improves cathepsin C/granzyme B-driven cytotoxic effects on HIV-infected cells during coinfectionpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue15pt_PT
oaire.citation.titleInternational Journal of Molecular Sciencespt_PT
oaire.citation.volume25pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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