Macrophage metallothioneins participate in the antileishmanial activity of antimonials
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 intr...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Parasitology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fpara.2023.1242727/full |
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| author | Deninson Alejandro Vargas Deninson Alejandro Vargas David J. Gregory Roni Nitzan Koren Dan Zilberstein Ashton Trey Belew Ashton Trey Belew Najib M. El-Sayed Najib M. El-Sayed María Adelaida Gómez María Adelaida Gómez |
| author_facet | Deninson Alejandro Vargas Deninson Alejandro Vargas David J. Gregory Roni Nitzan Koren Dan Zilberstein Ashton Trey Belew Ashton Trey Belew Najib M. El-Sayed Najib M. El-Sayed María Adelaida Gómez María Adelaida Gómez |
| author_sort | Deninson Alejandro Vargas |
| collection | DOAJ |
| description | 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 Leishmania upon exposure to pentavalent antimonials (SbV). Primary macrophages from patients with cutaneous leishmaniasis (CL) (n=6) were exposed ex vivo to L. V. panamensis infection and SbV, 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 Leishmania, 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 SbV, 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 SbV, intracellular survival of Leishmania in MTF-1KD cells was significantly enhanced. Results from this study highlight the participation of macrophage MTs in Sb-dependent parasite killing. |
| first_indexed | 2024-03-11T19:59:18Z |
| format | Article |
| id | doaj.art-3a3e86c308f74579b3e15cd09ab1ca59 |
| institution | Directory Open Access Journal |
| issn | 2813-2424 |
| language | English |
| last_indexed | 2024-03-11T19:59:18Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Parasitology |
| spelling | doaj.art-3a3e86c308f74579b3e15cd09ab1ca592023-10-04T10:00:55ZengFrontiers Media S.A.Frontiers in Parasitology2813-24242023-10-01210.3389/fpara.2023.12427271242727Macrophage metallothioneins participate in the antileishmanial activity of antimonialsDeninson Alejandro Vargas0Deninson Alejandro Vargas1David J. Gregory2Roni Nitzan Koren3Dan Zilberstein4Ashton Trey Belew5Ashton Trey Belew6Najib M. El-Sayed7Najib M. El-Sayed8María Adelaida Gómez9María Adelaida Gómez10Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Cali, ColombiaUniversidad Icesi, Cali, ColombiaDepartment of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, United StatesFaculty of Biology, Technion-Israel Institute of Technology, Haifa, IsraelFaculty of Biology, Technion-Israel Institute of Technology, Haifa, IsraelDepartment of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, United StatesCenter for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, United StatesDepartment of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD, United StatesCenter for Bioinformatics and Computational Biology, University of Maryland, College Park, MD, United StatesCentro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Cali, ColombiaUniversidad Icesi, Cali, ColombiaHost 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 Leishmania upon exposure to pentavalent antimonials (SbV). Primary macrophages from patients with cutaneous leishmaniasis (CL) (n=6) were exposed ex vivo to L. V. panamensis infection and SbV, 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 Leishmania, 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 SbV, 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 SbV, intracellular survival of Leishmania in MTF-1KD cells was significantly enhanced. Results from this study highlight the participation of macrophage MTs in Sb-dependent parasite killing.https://www.frontiersin.org/articles/10.3389/fpara.2023.1242727/fullmetallothioneinsmetal transcription factor-1 (MTF-1)leishmaniaantimonyhost-parasite interaction |
| spellingShingle | Deninson Alejandro Vargas Deninson Alejandro Vargas David J. Gregory Roni Nitzan Koren Dan Zilberstein Ashton Trey Belew Ashton Trey Belew Najib M. El-Sayed Najib M. El-Sayed María Adelaida Gómez María Adelaida Gómez Macrophage metallothioneins participate in the antileishmanial activity of antimonials Frontiers in Parasitology metallothioneins metal transcription factor-1 (MTF-1) leishmania antimony host-parasite interaction |
| title | Macrophage metallothioneins participate in the antileishmanial activity of antimonials |
| title_full | Macrophage metallothioneins participate in the antileishmanial activity of antimonials |
| title_fullStr | Macrophage metallothioneins participate in the antileishmanial activity of antimonials |
| title_full_unstemmed | Macrophage metallothioneins participate in the antileishmanial activity of antimonials |
| title_short | Macrophage metallothioneins participate in the antileishmanial activity of antimonials |
| title_sort | macrophage metallothioneins participate in the antileishmanial activity of antimonials |
| topic | metallothioneins metal transcription factor-1 (MTF-1) leishmania antimony host-parasite interaction |
| url | https://www.frontiersin.org/articles/10.3389/fpara.2023.1242727/full |
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