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dc.contributor.authorTaylor, MCen_US
dc.contributor.authorLewis, MDen_US
dc.contributor.authorFortes Francisco, Aen_US
dc.contributor.authorWilkinson, SRen_US
dc.contributor.authorKelly, JMen_US
dc.date.accessioned2015-04-28T14:17:44Z
dc.date.available2015-03-17en_US
dc.date.issued2015-04en_US
dc.identifier.urihttp://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0003707
dc.identifier.urihttp://qmro.qmul.ac.uk/xmlui/handle/123456789/7339
dc.descriptionPMID: 25875298 PMCID: PMC4395405 Wellcome Trust (Grant 084175) (http://www.wellcome.ac.uk/) and the British Heart Foundation (Grant PG/13/88/30556) (http://www.bhf.org.uk/). AFF was in receipt of a Brazilian National Council for Scientific and Technological Development (CNPq) fellowship (http://www.cnpq.br/).
dc.descriptionPMID: 25875298 PMCID: PMC4395405 Wellcome Trust (Grant 084175) (http://www.wellcome.ac.uk/) and the British Heart Foundation (Grant PG/13/88/30556) (http://www.bhf.org.uk/). AFF was in receipt of a Brazilian National Council for Scientific and Technological Development (CNPq) fellowship (http://www.cnpq.br/).
dc.description.abstractBACKGROUND: The neglected parasitic infection Chagas disease is rapidly becoming a globalised public health issue due to migration. There are only two anti-parasitic drugs available to treat this disease, benznidazole and nifurtimox. Thus it is important to identify and validate new drug targets in Trypanosoma cruzi, the causative agent. T. cruzi expresses an ER-localised ascorbate-dependent peroxidase (TcAPx). This parasite-specific enzyme has attracted interest from the perspective of targeted chemotherapy. METHODOLOGY/PRINCIPAL FINDINGS: To assess the importance of TcAPx in protecting T. cruzi from oxidative stress and to determine if it is essential for virulence, we generated null mutants by targeted gene disruption. Loss of activity was associated with increased sensitivity to exogenous hydrogen peroxide, but had no effect on susceptibility to the front-line Chagas disease drug benznidazole. This suggests that increased oxidative stress in the ER does not play a significant role in its mechanism of action. Homozygous knockouts could proceed through the entire life-cycle in vitro, although they exhibited a significant decrease in their ability to infect mammalian cells. To investigate virulence, we exploited a highly sensitive bioluminescence imaging system which allows parasites to be monitored in real-time in the chronic stage of murine infections. This showed that depletion of enzyme activity had no effect on T. cruzi replication, dissemination or tissue tropism in vivo. CONCLUSIONS/SIGNIFICANCE: TcAPx is not essential for parasite viability within the mammalian host, does not have a significant role in establishment or maintenance of chronic infections, and should therefore not be considered a priority for drug design.en_US
dc.description.sponsorshipThis work was supported by the Wellcome Trust (Grant 084175) (http://www.wellcome.ac.uk/) and the British Heart Foundation (Grant PG/13/88/30556) (http://www.bhf.org.uk/). AFF was in receipt of a Brazilian National Council for Scientific and Technological Development (CNPq) fellowship (http://www.cnpq.br/)en_US
dc.format.extente0003707 - ?en_US
dc.languageengen_US
dc.language.isoenen_US
dc.relation.ispartofPLoS Negl Trop Disen_US
dc.subjectAnimalsen_US
dc.subjectAscorbic Aciden_US
dc.subjectEndoplasmic Reticulumen_US
dc.subjectGene Deletionen_US
dc.subjectGene Expression Regulation, Enzymologicen_US
dc.subjectHydrogen Peroxideen_US
dc.subjectLuminescent Measurementsen_US
dc.subjectMiceen_US
dc.subjectNitroimidazolesen_US
dc.subjectOxidative Stressen_US
dc.subjectPeroxidasesen_US
dc.subjectTrypanocidal Agentsen_US
dc.subjectTrypanosoma cruzien_US
dc.subjectVirulenceen_US
dc.titleThe Trypanosoma cruzi vitamin C dependent peroxidase confers protection against oxidative stress but is not a determinant of virulence.en_US
dc.typeArticle
dc.identifier.doi10.1371/journal.pntd.0003707en_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/25875298en_US
pubs.issue4en_US
pubs.notesNo embargoen_US
pubs.publication-statusPublished onlineen_US
pubs.volume9en_US
dcterms.dateAccepted2015-03-17en_US


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