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
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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:
Nanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Minist Educ, Key Lab Integrated Management Crop Dis & Pests, Nanjing 210095, Jiangsu, Peoples R ChinaNanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Wang, Jingzhen
Yin, Ziyi
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Nanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Minist Educ, Key Lab Integrated Management Crop Dis & Pests, Nanjing 210095, Jiangsu, Peoples R ChinaNanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Yin, Ziyi
Tang, Wei
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机构:
Nanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Minist Educ, Key Lab Integrated Management Crop Dis & Pests, Nanjing 210095, Jiangsu, Peoples R ChinaNanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Tang, Wei
Cai, Xingjia
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机构:
Nanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Minist Educ, Key Lab Integrated Management Crop Dis & Pests, Nanjing 210095, Jiangsu, Peoples R ChinaNanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Cai, Xingjia
Gao, Chuyun
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机构:
Nanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Minist Educ, Key Lab Integrated Management Crop Dis & Pests, Nanjing 210095, Jiangsu, Peoples R ChinaNanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Gao, Chuyun
Zhang, Haifeng
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Nanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Minist Educ, Key Lab Integrated Management Crop Dis & Pests, Nanjing 210095, Jiangsu, Peoples R ChinaNanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Zhang, Haifeng
Zheng, Xiaobo
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Nanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Minist Educ, Key Lab Integrated Management Crop Dis & Pests, Nanjing 210095, Jiangsu, Peoples R ChinaNanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Zheng, Xiaobo
Wang, Ping
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机构:
Louisiana State Univ, Hlth Sci Ctr, Dept Pediat, New Orleans, LA 70112 USA
Louisiana State Univ, Hlth Sci Ctr, Dept Microbiol Immunol & Parasitol, New Orleans, LA 70112 USANanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Wang, Ping
Zhang, Zhengguang
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机构:
Nanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
Minist Educ, Key Lab Integrated Management Crop Dis & Pests, Nanjing 210095, Jiangsu, Peoples R ChinaNanjing Agr Univ, Dept Plant Pathol, Coll Plant Protect, Nanjing 210095, Jiangsu, Peoples R China
机构:
Poznan Univ Life Sci, Dept Biotechnol & Food Microbiol, 48 Wojska Polskiego St, PL-60627 Poznan, PolandPoznan Univ Life Sci, Dept Biotechnol & Food Microbiol, 48 Wojska Polskiego St, PL-60627 Poznan, Poland
Kowalska, Katarzyna
Olejnik, Anna
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Poznan Univ Life Sci, Dept Biotechnol & Food Microbiol, 48 Wojska Polskiego St, PL-60627 Poznan, PolandPoznan Univ Life Sci, Dept Biotechnol & Food Microbiol, 48 Wojska Polskiego St, PL-60627 Poznan, Poland
机构:
Univ Roma La Sapienza, Dip Med Interna DMISM, I-00185 Rome, Italy
Univ Roma La Sapienza, Life Nanosci Lab, I-00185 Rome, Italy
Univ Roma La Sapienza, EAL Inserm U 785, I-00185 Rome, ItalyUniv Roma La Sapienza, Dip Med Interna DMISM, I-00185 Rome, Italy
Pediconi, N.
Piconese, S.
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Univ Roma La Sapienza, Dip Med Interna DMISM, I-00185 Rome, ItalyUniv Roma La Sapienza, Dip Med Interna DMISM, I-00185 Rome, Italy
Piconese, S.
Valente, S.
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Univ Roma La Sapienza, Dip Chim & Tecnol Farmaco, I-00185 Rome, ItalyUniv Roma La Sapienza, Dip Med Interna DMISM, I-00185 Rome, Italy
Valente, S.
Di Cocco, S.
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Univ Roma La Sapienza, Dip Med Interna DMISM, I-00185 Rome, ItalyUniv Roma La Sapienza, Dip Med Interna DMISM, I-00185 Rome, Italy
Di Cocco, S.
Rotili, D.
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Univ Roma La Sapienza, Dip Chim & Tecnol Farmaco, I-00185 Rome, ItalyUniv Roma La Sapienza, Dip Med Interna DMISM, I-00185 Rome, Italy
Rotili, D.
Barnaba, V.
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Univ Roma La Sapienza, Dip Chim & Tecnol Farmaco, I-00185 Rome, ItalyUniv Roma La Sapienza, Dip Med Interna DMISM, I-00185 Rome, Italy
Barnaba, V.
Mai, A.
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Univ Roma La Sapienza, Dip Chim & Tecnol Farmaco, I-00185 Rome, ItalyUniv Roma La Sapienza, Dip Med Interna DMISM, I-00185 Rome, Italy
Mai, A.
Levrero, M.
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机构:
Univ Roma La Sapienza, Dip Med Interna DMISM, I-00185 Rome, Italy
Univ Roma La Sapienza, Life Nanosci Lab, I-00185 Rome, Italy
Univ Roma La Sapienza, EAL Inserm U 785, I-00185 Rome, ItalyUniv Roma La Sapienza, Dip Med Interna DMISM, I-00185 Rome, Italy