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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| Vydáno v: | Frontiers in parasitology Ročník 2 |
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| Hlavní autoři: | , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
Switzerland
Frontiers Media S.A
2023
|
| Témata: | |
| ISSN: | 2813-2424, 2813-2424 |
| On-line přístup: | Získat plný text |
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| Shrnutí: | 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 (Sb
V
). Primary macrophages from patients with cutaneous leishmaniasis (CL) (n=6) were exposed
ex vivo
to
L. V. panamensis
infection and Sb
V
, 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 Sb
V
, 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
V
, intracellular survival of
Leishmania
in MTF-1
KD
cells was significantly enhanced. Results from this study highlight the participation of macrophage MTs in Sb-dependent parasite killing. |
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| Bibliografie: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 All authors contributed equally to the design, discussion, review of results and approval of the final version of the manuscript. DV developed the entire experimental component. AB and NES performed RNA-seq and supported bioinformatics analysis. DG support the design and implementation of RNA interference assays using shRNA. All authors contributed to the article and approved the submitted version. Author contributions |
| ISSN: | 2813-2424 2813-2424 |
| DOI: | 10.3389/fpara.2023.1242727 |