{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:18:36Z","timestamp":1760145516722,"version":"build-2065373602"},"reference-count":59,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T00:00:00Z","timestamp":1721952000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","doi-asserted-by":"publisher","award":["PTDC\/SAU-INF\/28182\/2017","EXPL\/SAU-INF\/0742\/2021","UIDB\/04138\/2020","UIDB\/04279\/2020","CEECINST\/00070\/2021","2021.07978.BD","SFRH\/BD\/131948\/2017"],"award-info":[{"award-number":["PTDC\/SAU-INF\/28182\/2017","EXPL\/SAU-INF\/0742\/2021","UIDB\/04138\/2020","UIDB\/04279\/2020","CEECINST\/00070\/2021","2021.07978.BD","SFRH\/BD\/131948\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cystatin 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 \u03b3 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.<\/jats:p>","DOI":"10.3390\/ijms25158141","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T06:17:44Z","timestamp":1721974664000},"page":"8141","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cystatin F Depletion in Mycobacterium tuberculosis-Infected Macrophages Improves Cathepsin C\/Granzyme B-Driven Cytotoxic Effects on HIV-Infected Cells during Coinfection"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3997-9618","authenticated-orcid":false,"given":"Manoj","family":"Mandal","sequence":"first","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9602-1516","authenticated-orcid":false,"given":"David","family":"Pires","sequence":"additional","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"},{"name":"Center for Interdisciplinary Research in Health, Cat\u00f3lica Medical School, Universidade Cat\u00f3lica Portuguesa, Estrada Oct\u00e1vio Pato, 2635-631 Rio de Mouro, Portugal"}]},{"given":"Marta","family":"Calado","sequence":"additional","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7434-7208","authenticated-orcid":false,"given":"Jos\u00e9 Miguel","family":"Azevedo-Pereira","sequence":"additional","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5934-0198","authenticated-orcid":false,"given":"Elsa","family":"Anes","sequence":"additional","affiliation":[{"name":"Host-Pathogen Interactions Unit, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101","DOI":"10.2217\/fvl-2019-0069","article-title":"The Mtb-HIV Syndemic Interaction: Why Treating M. 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