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
  • [31] A thioredoxin reductase 1 inhibitor pyrano [3,2-a] phenazine inhibits A549 cells proliferation and migration through the induction of reactive oxygen species production
    Qifan Ding
    Hengyu Wang
    Ying Wang
    Yuanyuan Lu
    Molecular Biology Reports, 2022, 49 : 8835 - 8845
  • [32] A thioredoxin reductase 1 inhibitor pyrano [3,2-a] phenazine inhibits A549 cells proliferation and migration through the induction of reactive oxygen species production
    Ding, Qifan
    Wang, Hengyu
    Wang, Ying
    Lu, Yuanyuan
    MOLECULAR BIOLOGY REPORTS, 2022, 49 (09) : 8835 - 8845
  • [33] Overexpression of TaJAZ1 increases powdery mildew resistance through promoting reactive oxygen species accumulation in bread wheat
    Jing, Yexing
    Liu, Jie
    Liu, Pan
    Ming, Dongfeng
    Sun, Jiaqiang
    SCIENTIFIC REPORTS, 2019, 9 (1)
  • [34] Overexpression of TaJAZ1 increases powdery mildew resistance through promoting reactive oxygen species accumulation in bread wheat
    Yexing Jing
    Jie Liu
    Pan Liu
    Dongfeng Ming
    Jiaqiang Sun
    Scientific Reports, 9
  • [35] Biogenic silver nanoparticles reduce Toxoplasma gondii infection and proliferation in RAW 264.7 macrophages by inducing tumor necrosis factor-alpha and reactive oxygen species production in the cells
    da Silva Sanfelice, Raquel Arruda
    Silva, Taylon Felipe
    Tomiotto-Pellissier, Fernanda
    da Silva Bortoleti, Bruna Taciane
    Lazarin-Bidoia, Danielle
    Scandorieiro, Sara
    Nakazato, Gerson
    de Barros, Luiz Daniel
    Garcia, Joao Luis
    Verri, Waldiceu Aparecido
    Conchon-Costa, Ivete
    Pavanelli, Wander Rogerio
    Costa, Idessania Nazareth
    MICROBES AND INFECTION, 2022, 24 (05)
  • [36] Priming effects of tumor necrosis factor-α on production of reactive oxygen species during Toxoplasma gondii stimulation and receptor gene expression in differentiated HL-60 cells
    Kikuchi-Ueda, Takane
    Ubagai, Tsuneyuki
    Ono, Yasuo
    JOURNAL OF INFECTION AND CHEMOTHERAPY, 2013, 19 (06) : 1053 - 1064
  • [37] The P2X7 Receptor Mediates Toxoplasma gondii Control in Macrophages through Canonical NLRP3 Inflammasome Activation and Reactive Oxygen Species Production
    Abreu Moreira-Souza, Aline Cristina
    Coutinho Almeida-da-Silva, Cassio Luiz
    Rangel, Thuany Prado
    Rocha, Gabrielle da Costa
    Bellio, Maria
    Zamboni, Dario Simoes
    Vommaro, Rossiane Claudia
    Coutinho-Silva, Robson
    FRONTIERS IN IMMUNOLOGY, 2017, 8
  • [38] ROP16-Mediated Activation of STAT6 Suppresses Host Cell Reactive Oxygen Species Production, Facilitating Type III Toxoplasma gondii Growth and Survival
    Kochanowsky, Joshua A.
    Thomas, Kaitlin K.
    Koshy, Anita A.
    MBIO, 2021, 12 (02): : 1 - 17
  • [39] Inhibition of Histone Deacetylase 10 Induces Thioredoxin-Interacting Protein and Causes Accumulation of Reactive Oxygen Species in SNU-620 Human Gastric Cancer Cells
    Lee, Ju-Hee
    Jeong, Eun-Goo
    Choi, Moon-Chang
    Kim, Sung-Hak
    Park, Jung-Hyun
    Song, Sang-Hyun
    Park, Jinah
    Bang, Yung-Jue
    Kim, Tae-You
    MOLECULES AND CELLS, 2010, 30 (02) : 107 - 112
  • [40] The Wheat Annexin TaAnn12 Plays Positive Roles in Plant Disease Resistance by Regulating the Accumulation of Reactive Oxygen Species and Callose
    Shi, Beibei
    Liu, Weijian
    Ma, Qing
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2023, 24 (22)