Auranofin Resistance in Toxoplasma gondii Decreases the Accumulation of Reactive Oxygen Species but Does Not Target Parasite Thioredoxin Reductase

被引:9
|
作者
Ma, Christopher I. [1 ]
Tirtorahardjo, James A. [2 ]
Jan, Sharon [2 ]
Schweizer, Sakura S. [1 ,3 ]
Rosario, Shawn A. C. [3 ]
Du, Yanmiao [3 ]
Zhang, Jerry J. [1 ]
Morrissette, Naomi S. [4 ]
Andrade, Rosa M. [1 ,2 ]
机构
[1] Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA
[2] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA
[3] Univ Calif Irvine, Sch Biol Sci, Irvine, CA 92717 USA
[4] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA
关键词
gold; repurposing; anti-parasitic; resistance; redox; Toxoplasma; auranofin; superoxide;
D O I
10.3389/fcimb.2021.618994
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Auranofin, a reprofiled FDA-approved drug originally designed to treat rheumatoid arthritis, has emerged as a promising anti-parasitic drug. It induces the accumulation of reactive oxygen species (ROS) in parasites, including Toxoplasma gondii. We generated auranofin resistant T. gondii lines through chemical mutagenesis to identify the molecular target of this drug. Resistant clones were confirmed with a competition assay using wild-type T. gondii expressing yellow fluorescence protein (YFP) as a reference strain. The predicted auranofin target, thioredoxin reductase, was not mutated in any of our resistant lines. Subsequent whole genomic sequencing analysis (WGS) did not reveal a consensus resistance locus, although many have point mutations in genes encoding redox-relevant proteins such as superoxide dismutase (TgSOD2) and ribonucleotide reductase. We investigated the SOD2 L201P mutation and found that it was not sufficient to confer resistance when introduced into wild-type parasites. Resistant clones accumulated less ROS than their wild type counterparts. Our results demonstrate that resistance to auranofin in T. gondii enhances its ability to abate oxidative stress through diverse mechanisms. This evidence supports a hypothesized mechanism of auranofin anti-parasitic activity as disruption of redox homeostasis.
引用
收藏
页数:11
相关论文
共 50 条
  • [41] Sex difference in GPER expression does not change vascular relaxation or reactive oxygen species generation in rat mesenteric resistance arteries
    Peixoto, Pollyana
    da Silva, Josiane Fernandes
    Aires, Rosaria Dias
    Costa, Eduardo Damasceno
    Lemos, Virginia Soares
    Bissoli, Nazare Souza
    dos Santos, Roger Lyrio
    LIFE SCIENCES, 2018, 211 : 198 - 205
  • [42] The thioredoxin MoTrx2 protein mediates reactive oxygen species (ROS) balance and controls pathogenicity as a target of the transcription factor MoAP1 in Magnaporthe oryzae
    Wang, Jingzhen
    Yin, Ziyi
    Tang, Wei
    Cai, Xingjia
    Gao, Chuyun
    Zhang, Haifeng
    Zheng, Xiaobo
    Wang, Ping
    Zhang, Zhengguang
    MOLECULAR PLANT PATHOLOGY, 2017, 18 (09) : 1199 - 1209
  • [43] Rosehip Extract Decreases Reactive Oxygen Species Production and Lipid Accumulation in Hypertrophic 3T3-L1 Adipocytes with the Modulation of Inflammatory State
    Kowalska, Katarzyna
    Olejnik, Anna
    NUTRIENTS, 2024, 16 (19)
  • [44] Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice
    S. Paglialunga
    B. van Bree
    M. Bosma
    M. P. Valdecantos
    E. Amengual-Cladera
    J. A. Jörgensen
    D. van Beurden
    G. J. M. den Hartog
    D. M. Ouwens
    J. J. Briedé
    P. Schrauwen
    J. Hoeks
    Diabetologia, 2012, 55 : 2759 - 2768
  • [45] Targeting of mitochondrial reactive oxygen species production does not avert lipid-induced insulin resistance in muscle tissue from mice
    Paglialunga, S.
    van Bree, B.
    Bosma, M.
    Valdecantos, M. P.
    Amengual-Cladera, E.
    Jorgensen, J. A.
    van Beurden, D.
    den Hartog, G. J. M.
    Ouwens, D. M.
    Briede, J. J.
    Schrauwen, P.
    Hoeks, J.
    DIABETOLOGIA, 2012, 55 (10) : 2759 - 2768
  • [46] MC2791, A SPECIFIC Sirt1 AGONIST DRUG, DECREASES LIPIDS AND REACTIVE OXYGEN SPECIES ACCUMULATION IN AN IN VITRO MODEL OF STEATOSIS IN DIFFERENTIATED HepaRG CELLS
    Pediconi, N.
    Piconese, S.
    Valente, S.
    Di Cocco, S.
    Rotili, D.
    Barnaba, V.
    Mai, A.
    Levrero, M.
    JOURNAL OF HEPATOLOGY, 2013, 58 : S519 - S519
  • [47] Vitamin E but Not GSH Decreases Reactive Oxygen Species Accumulation and Enhances Sperm Production during In Vitro Maturation of Frozen-Thawed Prepubertal Mouse Testicular Tissue
    Arkoun, Brahim
    Galas, Ludovic
    Dumont, Ludovic
    Rives, Aurelie
    Saulnier, Justine
    Delessard, Marion
    Rondanino, Christine
    Rives, Nathalie
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2019, 20 (21)
  • [48] Cationic and Neutral N-Heterocyclic Carbene Gold(I) Complexes: Cytotoxicity, NCI-60 Screening, Cellular Uptake, Inhibition of Mammalian Thioredoxin Reductase, and Reactive Oxygen Species Formation
    Zhang, Chen
    Hemmert, Catherine
    Gornitzka, Heinz
    Cuvillier, Olivier
    Zhang, Ming
    Sun, Raymond Wai-Yin
    CHEMMEDCHEM, 2018, 13 (12) : 1218 - 1229
  • [49] Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species
    Produit-Zengaffinen, N.
    Davis-Lameloise, N.
    Perreten, H.
    Becard, D.
    Gjinovci, A.
    Keller, P. A.
    Wollheim, C. B.
    Herrera, P.
    Muzzin, P.
    Assimacopoulos-Jeannet, F.
    DIABETOLOGIA, 2007, 50 (01) : 84 - 93
  • [50] Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species
    N. Produit-Zengaffinen
    N. Davis-Lameloise
    H. Perreten
    D. Bécard
    A. Gjinovci
    P. A. Keller
    C. B. Wollheim
    P. Herrera
    P. Muzzin
    F. Assimacopoulos-Jeannet
    Diabetologia, 2007, 50 : 84 - 93