title: Mycobacterium tuberculosis Thioredoxin Reductase Is Essential for Thiol Redox Homeostasis but Plays a Minor Role in Antioxidant Defense.
abstract: Mycobacterium tuberculosis (Mtb) must cope with exogenous oxidative stress imposed by the host. Unlike other antioxidant enzymes, Mtb's thioredoxin reductase TrxB2 has been predicted to be essential not only to fight host defenses but also for in vitro growth. However, the specific physiological role of TrxB2 and its importance for Mtb pathogenesis remain undefined. Here we show that genetic inactivation of thioredoxin reductase perturbed several growth-essential processes, including sulfur and DNA metabolism and rapidly killed and lysed Mtb. Death was due to cidal thiol-specific oxidizing stress and prevented by a disulfide reductant. In contrast, thioredoxin reductase deficiency did not significantly increase susceptibility to oxidative and nitrosative stress. In vivo targeting TrxB2 eradicated Mtb during both acute and chronic phases of mouse infection. Deliberately leaky knockdown mutants identified the specificity of TrxB2 inhibitors and showed that partial inactivation of TrxB2 increased Mtb's susceptibility to rifampicin. These studies reveal TrxB2 as essential thiol-reducing enzyme in Mtb in vitro and during infection, establish the value of targeting TrxB2, and provide tools to accelerate the development of TrxB2 inhibitors.
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.|Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States of America.
authors.forename: Kan
authors.initials: K
authors.lastname: Lin
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: O'Brien
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Carolina
authors.initials: C
authors.lastname: Trujillo
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.|Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States of America.
authors.forename: Ruojun
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Wallach
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schnappinger
authors.affiliation: Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, United States of America.|Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, United States of America.
authors.forename: Sabine
authors.identifier: 0000-0002-7951-2310
authors.initials: S
authors.lastname: Ehrt
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism*; D014376:Tuberculosis / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D013880:Thioredoxin-Disulfide Reductase