Auranofin Resistance in Toxoplasma gondii Decreases the Accumulation of Reactive Oxygen Species but Does Not Target Parasite Thioredoxin Reductase
被引:9
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作者:
Ma, Christopher I.
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Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USAUniv Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA
Ma, Christopher I.
[1
]
Tirtorahardjo, James A.
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Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USAUniv Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA
Tirtorahardjo, James A.
[2
]
Jan, Sharon
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Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USAUniv Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA
Jan, Sharon
[2
]
Schweizer, Sakura S.
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Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA
Univ Calif Irvine, Sch Biol Sci, Irvine, CA 92717 USAUniv Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA
Schweizer, Sakura S.
[1
,3
]
Rosario, Shawn A. C.
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Univ Calif Irvine, Sch Biol Sci, Irvine, CA 92717 USAUniv Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA
Rosario, Shawn A. C.
[3
]
Du, Yanmiao
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Univ Calif Irvine, Sch Biol Sci, Irvine, CA 92717 USAUniv Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA
Du, Yanmiao
[3
]
Zhang, Jerry J.
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Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USAUniv Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA
Zhang, Jerry J.
[1
]
Morrissette, Naomi S.
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Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USAUniv Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA
Morrissette, Naomi S.
[4
]
Andrade, Rosa M.
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Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA
Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USAUniv Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92717 USA
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
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.
机构:
Univ Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Immunobiol Program, Rio De Janeiro, Brazil
Univ Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Parasitol & Cell Biol Program, Rio De Janeiro, BrazilUniv Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Immunobiol Program, Rio De Janeiro, Brazil
Abreu Moreira-Souza, Aline Cristina
Coutinho Almeida-da-Silva, Cassio Luiz
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Univ Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Immunobiol Program, Rio De Janeiro, BrazilUniv Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Immunobiol Program, Rio De Janeiro, Brazil
Coutinho Almeida-da-Silva, Cassio Luiz
Rangel, Thuany Prado
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机构:
Univ Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Immunobiol Program, Rio De Janeiro, Brazil
Univ Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Parasitol & Cell Biol Program, Rio De Janeiro, BrazilUniv Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Immunobiol Program, Rio De Janeiro, Brazil
Rangel, Thuany Prado
Rocha, Gabrielle da Costa
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Univ Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Immunobiol Program, Rio De Janeiro, BrazilUniv Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Immunobiol Program, Rio De Janeiro, Brazil
Rocha, Gabrielle da Costa
Bellio, Maria
论文数: 0引用数: 0
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机构:
Univ Fed Rio de Janeiro, Inst Microbiol Paulo de Goes, Dept Immunol, Rio De Janeiro, BrazilUniv Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Immunobiol Program, Rio De Janeiro, Brazil
Bellio, Maria
Zamboni, Dario Simoes
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Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Cell Biol, Sao Paulo, BrazilUniv Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Immunobiol Program, Rio De Janeiro, Brazil
Zamboni, Dario Simoes
Vommaro, Rossiane Claudia
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Univ Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Parasitol & Cell Biol Program, Rio De Janeiro, BrazilUniv Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Immunobiol Program, Rio De Janeiro, Brazil
Vommaro, Rossiane Claudia
Coutinho-Silva, Robson
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Univ Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Immunobiol Program, Rio De Janeiro, BrazilUniv Fed Rio de Janeiro, Biophys Inst Carlos Chagas Filho, Immunobiol Program, Rio De Janeiro, Brazil
机构:
Univ Arizona, Dept Immunobiol, Tucson, AZ 85721 USAUniv Arizona, Dept Immunobiol, Tucson, AZ 85721 USA
Kochanowsky, Joshua A.
Thomas, Kaitlin K.
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Univ Arizona, BIO5 Inst, Tucson, AZ 85721 USAUniv Arizona, Dept Immunobiol, Tucson, AZ 85721 USA
Thomas, Kaitlin K.
Koshy, Anita A.
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Univ Arizona, Dept Immunobiol, Tucson, AZ 85721 USA
Univ Arizona, BIO5 Inst, Tucson, AZ 85721 USA
Univ Arizona, Dept Neurol, Tucson, AZ 85721 USAUniv Arizona, Dept Immunobiol, Tucson, AZ 85721 USA
机构:
Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South KoreaSeoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea
Lee, Ju-Hee
Jeong, Eun-Goo
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Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South KoreaSeoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea
Jeong, Eun-Goo
Choi, Moon-Chang
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Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South KoreaSeoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea
Choi, Moon-Chang
Kim, Sung-Hak
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Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South KoreaSeoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea
Kim, Sung-Hak
Park, Jung-Hyun
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Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South KoreaSeoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea
Park, Jung-Hyun
Song, Sang-Hyun
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Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South KoreaSeoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea
Song, Sang-Hyun
Park, Jinah
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Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South KoreaSeoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea
Park, Jinah
Bang, Yung-Jue
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Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea
Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 110799, South Korea
Seoul Natl Univ, Dept Mol Med & Biopharmaceut Sci, Grad Sch Convergence Sci & Technol, Seoul 151742, South KoreaSeoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea
Bang, Yung-Jue
Kim, Tae-You
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机构:
Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea
Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 110799, South Korea
Seoul Natl Univ, Dept Mol Med & Biopharmaceut Sci, Grad Sch Convergence Sci & Technol, Seoul 151742, South KoreaSeoul Natl Univ, Coll Med, Canc Res Inst, Seoul 110799, South Korea
机构:
Yanan Univ, Coll Life Sci, Shaanxi Key Lab Chinese Jujube, Yanan 716000, Peoples R China
Northwest A&F Univ, Coll Plant Protect, State Key Lab Crop Stress Biol Arid Areas, Yangling 712100, Peoples R ChinaYanan Univ, Coll Life Sci, Shaanxi Key Lab Chinese Jujube, Yanan 716000, Peoples R China
Shi, Beibei
Liu, Weijian
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Yanan Univ, Coll Life Sci, Shaanxi Key Lab Chinese Jujube, Yanan 716000, Peoples R ChinaYanan Univ, Coll Life Sci, Shaanxi Key Lab Chinese Jujube, Yanan 716000, Peoples R China
Liu, Weijian
Ma, Qing
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机构:
Northwest A&F Univ, Coll Plant Protect, State Key Lab Crop Stress Biol Arid Areas, Yangling 712100, Peoples R ChinaYanan Univ, Coll Life Sci, Shaanxi Key Lab Chinese Jujube, Yanan 716000, Peoples R China