PMID- 38239429
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240210
IS  - 2813-2424 (Electronic)
IS  - 2813-2424 (Linking)
VI  - 2
DP  - 2023
TI  - Macrophage metallothioneins participate in the antileishmanial activity of 
      antimonials.
LID - 1242727 [pii]
LID - 10.3389/fpara.2023.1242727 [doi]
AB  - 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.
FAU - Vargas, Deninson Alejandro
AU  - Vargas DA
AD  - Centro Internacional de Entrenamiento e Investigaciones Medicas (CIDEIM), Cali, 
      Colombia.
AD  - Universidad Icesi, Cali, Colombia.
FAU - Gregory, David J
AU  - Gregory DJ
AD  - Department of Environmental Health, Harvard T.H. Chan School of Public Health, 
      Boston, MA, United States.
FAU - Koren, Roni Nitzan
AU  - Koren RN
AD  - Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
FAU - Zilberstein, Dan
AU  - Zilberstein D
AD  - Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
FAU - Belew, Ashton Trey
AU  - Belew AT
AD  - Department of Cell Biology and Molecular Genetics, University of Maryland, 
      College Park, MD, United States.
AD  - Center for Bioinformatics and Computational Biology, University of Maryland, 
      College Park, MD, United States.
FAU - El-Sayed, Najib M
AU  - El-Sayed NM
AD  - Department of Cell Biology and Molecular Genetics, University of Maryland, 
      College Park, MD, United States.
AD  - Center for Bioinformatics and Computational Biology, University of Maryland, 
      College Park, MD, United States.
FAU - Gomez, Maria Adelaida
AU  - Gomez MA
AD  - Centro Internacional de Entrenamiento e Investigaciones Medicas (CIDEIM), Cali, 
      Colombia.
AD  - Universidad Icesi, Cali, Colombia.
LA  - eng
GR  - WT_/Wellcome Trust/United Kingdom
GR  - D43 TW006589/TW/FIC NIH HHS/United States
GR  - R01 AI104823/AI/NIAID NIH HHS/United States
GR  - U19 AI129910/AI/NIAID NIH HHS/United States
PT  - Journal Article
DEP - 20231004
PL  - Switzerland
TA  - Front Parasitol
JT  - Frontiers in parasitology
JID - 9918573587206676
PMC - PMC10795579
MID - NIHMS1955141
OTO - NOTNLM
OT  - antimony
OT  - host-parasite interaction
OT  - leishmania
OT  - metal transcription factor-1 (MTF-1)
OT  - metallothioneins
COIS- Conflict of interest The authors declare that the research was conducted in the 
      absence of any commercial or financial relationships that could be construed as a 
      potential conflict of interest.
EDAT- 2024/01/19 06:43
MHDA- 2024/01/19 06:44
PMCR- 2024/01/18
CRDT- 2024/01/19 03:39
PHST- 2024/01/19 06:44 [medline]
PHST- 2024/01/19 06:43 [pubmed]
PHST- 2024/01/19 03:39 [entrez]
PHST- 2024/01/18 00:00 [pmc-release]
AID - 1242727 [pii]
AID - 10.3389/fpara.2023.1242727 [doi]
PST - ppublish
SO  - Front Parasitol. 2023;2:1242727. doi: 10.3389/fpara.2023.1242727. Epub 2023 Oct 
      4.