Thioredoxin 1 Participates in the Activity of the<i>Salmonella enterica</i>Serovar Typhimurium Pathogenicity Island 2 Type III Secretion System

Negrea, Aurel; Bjur, Eva; Puiac, Speranta; Ygberg, Sofia; Åslund, Fredrik; Rhen, Mikael

doi:10.1128/jb.00532-09

Cited by 19 publications

(24 citation statements)

References 57 publications

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“…These investigations indicate that thioredoxin-1 does not depend on its well-characterized thiol-disulfide oxidoreductase to support SPI2 expression needed for the intracellular growth of Salmonella . These findings are consistent with previous published work that showed a role for TrxA in regulation of SPI2 function (Negrea et al, 2009). We also tested the survival of Salmonella expressing wild-type trxA or the trxA C32A C35A variant in primary macrophages producing large amounts of ROS through the enzymatic activity of the NADPH phagocyte oxidase (Fig.…”

Section: Resultssupporting

confidence: 94%

“…By directing electrons from NADPH and thioredoxin reductase to disulfide bonds in target proteins, thioredoxins maintain thiol redox homeostasis. Regulation of SPI2 expression by thioredoxin-1 is critical to Salmonella pathogenesis (Bjur et al, 2006; Negrea et al, 2009), but the molecular mechanism by which thioredoxin-1 promotes SPI2 expression and Salmonella virulence is incompletely understood. The classical oxidoreductase activity of thioredoxin-1 promotes antioxidant defenses of Salmonella in vitro , but appears to be largely dispensable in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…Thioredoxin-mediated thiol-disulfide exchange reactions control the activity of a range of biomolecules, including ribonucleotide reductase, phosphoadenosine-phosphosulfate reductase, methionine sulfoxide reductase, and arsenate reductase (Holmgren, 1989). Thioredoxin-1 has been shown to regulate Salmonella ’s SPI2 type III secretion system (Negrea et al, 2009). How thioredoxin-1 controls SPI2 expression is currently unclear.…”

Section: Introductionmentioning

confidence: 99%

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Antioxidant Defense by Thioredoxin Can Occur Independently of Canonical Thiol-Disulfide Oxidoreductase Enzymatic Activity

et al. 2016

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Summary The thiol-disulfide oxidoreductase CXXC catalytic domain of thioredoxin contributes to antioxidant defense in phylogenetically diverse organisms. We find that while the oxidoreductase activity of thioredoxin-1 protects Salmonella enterica serovar Typhimurium from hydrogen peroxide in vitro, it does not appear to contribute to Salmonella’s antioxidant defenses in vivo. Nonetheless, thioredoxin-1 defends Salmonella from oxidative stress resulting from NADPH phagocyte oxidase macrophage expression during the innate immune response in mice. Thioredoxin-1 binds to the flexible linker, which connects the receiver and effector domains of SsrB, thereby keeping this response regulator in the soluble fraction. Thioredoxin-1, independently of thiol-disulfide exchange, activates intracellular SPI2 gene transcription required for Salmonella resistance to both reactive species generated by NADPH phagocyte oxidase and oxygen-independent lysosomal host defenses. These findings suggest that the horizontally-acquired virulence determinant SsrB is regulated post-translationally by ancestrally-present thioredoxin.

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Section: Resultssupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antioxidant Defense by Thioredoxin Can Occur Independently of Canonical Thiol-Disulfide Oxidoreductase Enzymatic Activity

et al. 2016

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“…Salmonella and E. coli have two major redox systems to repair oxidized sulfhydryl groups in cytosolic proteins, namely the thioredoxin and glutathione/ glutaredoxin systems (Stewart et al, 1998). Previous studies have uncovered a link between the expression of thioredoxin 1 (TrxA) and Salmonella virulence, as a trxA deletion strain displayed a virulence defect in BALB/c mice and a cell culture model of murine macrophage-like cells (Bjur et al, 2006;Negrea et al, 2009). In the same work deletion of grxA was found to increase fitness of Salmonella in the macrophage model (Bjur et al, 2006).…”

Section: Rewiring the Regulatory Network Of Virulence Gene Expressionmentioning

confidence: 99%

Dual RNA-seq of pathogen and host

2012

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SummaryThe infection of a eukaryotic host cell by a bacterial pathogen is one of the most intimate examples of cross-kingdom interactions in biology. Infection processes are highly relevant from both a basic research as well as a clinical point of view. Sophisticated mechanisms have evolved in the pathogen to manipulate the host response and vice versa host cells have developed a wide range of anti-microbial defense strategies to combat bacterial invasion and clear infections.However, it is this diversity and complexity that makes infection research so challenging to technically address as common approaches have either been optimized for bacterial or eukaryotic organisms. Instead, methods are required that are able to deal with the often dramatic discrepancy between host and pathogen with respect to various cellular properties and processes. One class of cellular macromolecules that exemplify this host-pathogen heterogeneity is given by their transcriptomes: Bacterial transcripts differ from their eukaryotic counterparts in many aspects that involve both quantitative and qualitative traits. The entity of RNA transcripts present in a cell is of paramount interest as it reflects the cell's physiological state under the given condition. Genome-wide transcriptomic techniques such as RNA-seq have therefore been used for single-organism analyses for several years, but their applicability has been limited for infection studies.The present work describes the establishment of a novel transcriptomic approach for infection biology which we have termed "Dual RNA-seq". Using this technology, it was intended to shed light particularly on the contribution of non-protein-encoding transcripts to virulence, as these classes have mostly evaded previous infection studies due to the lack of suitable methods. The performance of Dual RNA-seq was evaluated in an in vitro infection model based on the important facultative intracellular pathogen Salmonella enterica serovar Typhimurium and different human cell lines. Dual RNA-seq was found to be capable of capturing all major bacterial and human transcript classes and proved reproducible. During the course of these experiments, a previously largely uncharacterized bacterial small non-coding RNA (sRNA), referred to as STnc440, was identified as one of the most strongly induced genes in intracellular Salmonella.Interestingly, while inhibition of STnc440 expression has been previously shown to cause a virulence defect in different animal models of Salmonellosis, the underlying molecular mechanisms have remained obscure. Here, classical genetics, transcriptomics and biochemical assays proposed a complex model of Salmonella gene expression control that is orchestrated by this sRNA. In particular, STnc440 was found to be involved in the regulation of multiple bacterial target mRNAs by direct base pair interaction with consequences for Salmonella virulence and

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“…The trxA mutant was attenuated for virulence when injected intraperitoneally into BALB/c mice in competition experiments at a 1:1 ratio with the wild-type parent strain, unlike trxC or trxB mutants in similar experiments, showing that Trx1 contributes to the virulence of S. Typhimurium (2). Negrea et al (29) have recently reported that thioredoxin 1 is required for the proper activity of the Salmonella pathogenicity island (SPI2) type III secretion system. However, these authors did not investigate the pathology caused by infection with a trxA mutant or whether the mutant offered protection against subsequent wild-type challenge.…”

Section: ؉ T Cells and B Lymphocytes In The Spleen And Reduced Infiltmentioning

confidence: 99%

Salmonella enterica Serovar Typhimurium trxA Mutants Are Protective against Virulent Challenge and Induce Less Inflammation than the Live-Attenuated Vaccine Strain SL3261

et al. 2010

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In Salmonella enterica serovar Typhimurium, trxA encodes thioredoxin 1, a small, soluble protein with disulfide reductase activity, which catalyzes thiol disulfide redox reactions in a variety of substrate proteins. Thioredoxins are involved as antioxidants in defense against oxidative stresses, such as exposure to hydrogen peroxide and hydroxyl radicals. We have made a defined, complete deletion of trxA in the mouse-virulent S. Typhimurium strain SL1344 (SL1344 trxA), replacing the gene with a kanamycin resistance gene cassette. SL1344 trxA was attenuated for virulence in BALB/c mice by the oral and intravenous routes and when used in immunization experiments provided protection against challenge with the virulent parent strain. SL1344 trxA induced less inflammation in murine spleens and livers than SL3261, the aroA mutant, live attenuated vaccine strain. The reduced splenomegaly observed following infection with SL1344 trxA was partially attributed to a reduction in the number of both CD4؉ and CD8 ؉ T cells and B lymphocytes in the spleen and reduced infiltration by CD11b؉ cells into the spleen compared with spleens from mice infected with SL3261. This less severe pathological response indicates that a trxA mutation might be used to reduce reactogenicity of live attenuated vaccine strains. We tested this by deleting trxA in SL3261. SL3261 trxA was also less inflammatory than SL3261 but was slightly less effective as a vaccine strain than either the SL3261 parent strain or SL1344 trxA.

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Thioredoxin 1 Participates in the Activity of theSalmonella entericaSerovar Typhimurium Pathogenicity Island 2 Type III Secretion System

Cited by 19 publications

References 57 publications

Antioxidant Defense by Thioredoxin Can Occur Independently of Canonical Thiol-Disulfide Oxidoreductase Enzymatic Activity

Antioxidant Defense by Thioredoxin Can Occur Independently of Canonical Thiol-Disulfide Oxidoreductase Enzymatic Activity

Dual RNA-seq of pathogen and host

Salmonella enterica Serovar Typhimurium trxA Mutants Are Protective against Virulent Challenge and Induce Less Inflammation than the Live-Attenuated Vaccine Strain SL3261

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