{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T14:09:50Z","timestamp":1791641390639,"version":"4.3.4"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T00:00:00Z","timestamp":1696377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Parasitol."],"abstract":"<jats:p>Host cell functions that participate in the pharmacokinetics and pharmacodynamics (PK\/PD) of drugs against intracellular pathogen infections are critical for drug efficacy. In this study, we investigated whether macrophage mechanisms of xenobiotic detoxification contribute to the elimination of intracellular <jats:italic>Leishmania<\/jats:italic> upon exposure to pentavalent antimonials (Sb<jats:sup>V<\/jats:sup>). Primary macrophages from patients with cutaneous leishmaniasis (CL) (n=6) were exposed <jats:italic>ex vivo<\/jats:italic> to <jats:italic>L. V. panamensis<\/jats:italic> infection and Sb<jats:sup>V<\/jats:sup>, and transcriptomes were generated. Seven metallothionein (MT) genes, potent scavengers of heavy metals and central elements of the mammalian cell machinery for xenobiotic detoxification, were within the top 20 up-regulated genes. To functionally validate the participation of MTs in drug-mediated killing of intracellular <jats:italic>Leishmania<\/jats:italic>, tandem knockdown (KD) of MT2-A and MT1-E, MT1-F, and MT1-X was performed using a pan-MT shRNA approach in THP-1 cells. Parasite survival was unaffected in tandem-KD cells, as a consequence of strong transcriptional upregulation of MTs by infection and Sb<jats:sup>V<\/jats:sup>, overcoming the KD effect. Gene silencing of the metal transcription factor-1 (MTF-1) abrogated expression of MT1 and MT2-A genes, but not ZnT-1. Upon exposure to Sb<jats:sup>V<\/jats:sup>, intracellular survival of <jats:italic>Leishmania<\/jats:italic> in MTF-1<jats:sup>KD<\/jats:sup> cells was significantly enhanced. Results from this study highlight the participation of macrophage MTs in Sb-dependent parasite killing.<\/jats:p>","DOI":"10.3389\/fpara.2023.1242727","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T10:01:07Z","timestamp":1696413667000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Macrophage metallothioneins participate in the antileishmanial activity of antimonials"],"prefix":"10.3389","volume":"2","author":[{"given":"Deninson Alejandro","family":"Vargas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Gregory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roni Nitzan","family":"Koren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Zilberstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashton Trey","family":"Belew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najib M.","family":"El-Sayed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Adelaida","family":"G\u00f3mez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,10,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0035671","article-title":"Leishmaniasis worldwide and global estimates of its incidence","volume":"7","author":"Alvar","year":"2012","journal-title":"PloS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq-A Python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"B3","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/S0006-2952(99)00301-9","article-title":"Regulation of metallothionein gene expression by oxidative stress and metal ions","volume":"59","author":"Andrews","year":"2000","journal-title":"Biochem. 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