Redox Balance Mechanisms in Schistosoma mansoni Rely on Peroxiredoxins and Albumin and Implicate Peroxiredoxins as Novel Drug Targets

Sayed, Ahmed A.; Cook, Shawna K.; Williams, David L.

doi:10.1074/jbc.m512601200

Cited by 110 publications

(121 citation statements)

References 54 publications

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“…Controlled, semi-quantitative reverse transcription (RT)-PCR was performed using cDNA generated from 1 μg total RNA from each parasite lifecycle developmental stage (cercariae, skin (4 hour, 24 hour, 5 day) and lung (10 day) schistosomulae, liver (23 day), adult (male and female), and egg) as described [31]. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH, M92359) was used as an internal loading control.…”

Section: Rna Expression Analysismentioning

confidence: 99%

Proteomic analysis of Schistosoma mansoni egg secretions

Cass

Johnson

Califf

et al. 2007

Molecular and Biochemical Parasitology

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192

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Schistosomiasis remains a largely neglected, global health problem. The morbid pathology of the disease stems from the host's inflammatory response to parasite eggs trapped in host tissues. Long term host/parasite survival is dependent upon the successful modulation of the acute pathological response, which is induced by egg antigens. In this study, using Multidimensional Protein Identification Technology, we identified the Schistosoma mansoni egg secretome consisting of 188 proteins. Notably we identified proteins involved in redox balance, molecular chaperoning and protein folding, development and signaling, scavenging and metabolic pathways, immune response modulation, and 32 novel, previously uncharacterized schistosome proteins. We localized a subset of previously-characterized schistosome proteins identified in egg secretions in this study, to the surface of live S. mansoni eggs using the circumoval precipitin reaction. The identification of proteins actively secreted by live schistosome eggs provides important new information for understanding immune modulation and the pathology of schistosomiasis.

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Section: Rna Expression Analysismentioning

confidence: 99%

Proteomic analysis of Schistosoma mansoni egg secretions

Cass

Johnson

Califf

et al. 2007

Molecular and Biochemical Parasitology

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192

196

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“…Although we cannot comment on the expression of antioxidants during the entire developmental cycle, a number of interesting points can be made. Peroxiredoxins appear to be the main hydrogen peroxide-reducing activity in the parasite (Sayed et al, 2006). Cytoplasmic peroxiredoxin 2 and mitochondrial peroxiredoxin 3 appear to be constitutively expressed in the stages profiled.…”

Section: Expression Analysismentioning

confidence: 99%

“…Schistosomes are thought to be especially sensitive to oxidative stress and antioxidant enzymes have been shown to play important roles in the host-parasite interaction (LoVerde, 1998;Sayed et al, 2006). Figure 5 illustrates the tag expression patterns for a number of antioxidant enzymes.…”

Section: Expression Analysismentioning

confidence: 99%

“…However, slow progress in the development of tools for manipulating specific gene expression in intact worms has impeded research efforts aimed at addressing important functional genomics questions. Currently RNA interference (RNAi) methods being applied to S. mansoni mammalian (Skelly et al, 2003;Correnti et al, 2005;Sayed et al, 2006) and snail (Boyle et al, 2003;Dinguirard and Yoshino, 2006) stages represent the most promising approach to date for gene manipulation in these parasites, although advances in schistosome transgenic technology recently have been reported (Grevelding, 2006;Kines et al, 2006;Brindley and Pearce, 2007) showing potential for application to functional gene studies.…”

Section: Expression Analysismentioning

confidence: 99%

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Profiling Schistosoma mansoni development using serial analysis of gene expression (SAGE)

Williams

Sayed

Bernier

et al. 2007

Experimental Parasitology

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Despite the widespread use of chemotherapy and other control strategies over the past 50 years, transmission rates for schistosomiasis have changed little. Regardless of the approach used, future control efforts will require a more complete understanding of fundamental parasite biology. Schistosomes undergo complex development involving an alteration of parasite generations within a mammalian and freshwater molluscan host in the completion of its lifecycle. Little is known about factors controlling schistosome development, but understanding these processes may facilitate the discovery of new control methods. Therefore, our goal in this study is to determine global developmentally-regulated and stage-specific gene expression in Schistosoma mansoni using Serial Analysis of Gene Expression (SAGE). We present a preliminary analysis of genes expressed during development and sexual differentiation in the mammalian host and during early larval development in the snail host. A number of novel, differentially expressed genes have been identified, both within and between the different developmental stages found in the mammalian and snail hosts.

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“…GPxs reduce H 2 O 2 and lipid hydroperoxides to water and the corresponding alcohols, respectively. There are two Sec-containing GPxs present in parasitic platyhelminth genomes corresponding to cytosolic and secreted isoforms, both of them most closely related to mammalian GPx4, which is active mostly against lipid peroxides (49). Indeed, the biochemically characterized GPx protein from S. mansoni is more active with lipid peroxides than with H 2 O 2 (35).…”

Section: Antioxidant Defenses In Platyhelminth Parasites Are More Prementioning

confidence: 99%

Thioredoxin Glutathione Reductase-Dependent Redox Networks in Platyhelminth Parasites

Williams

Bonilla²,

Gladyshev³

et al. 2013

Antioxidants & Redox Signaling

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Significance: Platyhelminth parasites cause chronic infections that are a major cause of disability, mortality, and economic losses in developing countries. Maintaining redox homeostasis is a major adaptive problem faced by parasites and its disruption can shift the biochemical balance toward the host. Platyhelminth parasites possess a streamlined thiol-based redox system in which a single enzyme, thioredoxin glutathione reductase (TGR), a fusion of a glutaredoxin (Grx) domain to canonical thioredoxin reductase (TR) domains, supplies electrons to oxidized glutathione (GSSG) and thioredoxin (Trx). TGR has been validated as a drug target for schistosomiasis. Recent Advances: In addition to glutathione (GSH) and Trx reduction, TGR supports GSH-independent deglutathionylation conferring an additional advantage to the TGR redox array. Biochemical and structural studies have shown that the TR activity does not require the Grx domain, while the glutathione reductase and deglutathionylase activities depend on the Grx domain, which receives electrons from the TR domains. The search for TGR inhibitors has identified promising drug leads, notably oxadiazole N-oxides. Critical Issues: A conspicuous feature of platyhelminth TGRs is that their Grx-dependent activities are temporarily inhibited at high GSSG concentrations. The mechanism underlying the phenomenon and its biological relevance are not completely understood. Future Directions: The functional diversity of Trxs and Grxs encoded in platyhelminth genomes remains to be further assessed to thoroughly understand the TGR-dependent redox network. Optimization of TGR inhibitors and identification of compounds targeting other parasite redox enzymes are good options to clinically develop relevant drugs for these neglected, but important diseases. Antioxid. Redox Signal. 19,[735][736][737][738][739][740][741][742][743][744][745]

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Redox Balance Mechanisms in Schistosoma mansoni Rely on Peroxiredoxins and Albumin and Implicate Peroxiredoxins as Novel Drug Targets

Cited by 110 publications

References 54 publications

Proteomic analysis of Schistosoma mansoni egg secretions

Proteomic analysis of Schistosoma mansoni egg secretions

Profiling Schistosoma mansoni development using serial analysis of gene expression (SAGE)

Thioredoxin Glutathione Reductase-Dependent Redox Networks in Platyhelminth Parasites

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