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Originally published In Press as doi:10.1074/jbc.M512601200 on April 10, 2006

J. Biol. Chem., Vol. 281, Issue 25, 17001-17010, June 23, 2006
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Redox Balance Mechanisms in Schistosoma mansoni Rely on Peroxiredoxins and Albumin and Implicate Peroxiredoxins as Novel Drug Targets*Formula

Ahmed A. Sayed, Shawna K. Cook, and David L. Williams1

From the Department of Biological Sciences, Illinois State University, Normal, Illinois 61790

Schistosoma mansoni, a causative agent of schistosomiasis, resides in the hepatic portal circulation of their human host up to 30 years without being eliminated by the host immune attack. Production of an antioxidant "firewall," which would neutralize the oxidative assault generated by host immune defenses, is one proposed survival mechanism of the parasite. Schistosomes lack catalase, the main H2O2-neutralizing enzyme of many organisms, and their glutathione peroxidases are in the phospholipid class with poor reactivity toward H2O2. Evidence implicates peroxiredoxins (Prx) as providing the main enzymatic activity to reduce H2O2 in the parasite. Quantitative monitoring of Prx mRNAs during parasite life cycle indicated that Prx proteins are differentially expressed, with highest expression occurring in adult stages (oxidative resistant stages). Incubation of schistosomula with Prx1 double-stranded RNA knocked down total Prx enzymatic activity and resulted in lowered survival of cultured parasites compared with controls demonstrating that Prx are essential parasite proteins. These results represent the first report of lethal gene silencing in Schistosoma. Investigation of downstream effects of Prx silencing revealed an abrupt increase of lipid peroxides and the generation of several oxidized proteins. Using mass spectrometry, parasite albumin and actin were identified as the main oxidized proteins. Gene expression analysis showed that schistosome albumin was induced by oxidative stress. This study highlights Prx proteins as essential parasite proteins and potential new targets for anti-schistosome drug development and albumin as a novel, sacrificial oxidant scavenging protein in parasite redox regulation.


Received for publication, November 28, 2005 , and in revised form, March 23, 2006.

* This work was supported in part by National Institutes of Health Grant AI-054403. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Formula The on-line version of this article (available at http://www.jbc.org) contains one supplemental figure.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AY729668 [GenBank] .

1 To whom correspondence should be addressed: Dept. of Biological Sciences, IL State University, Normal, IL 61790-4120. Tel.: 309-438-2608; Fax: 309-438-3722; E-mail: dlwilli{at}ilstu.edu.


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