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2015-02-06Zeitschriftenartikel DOI: 10.1371/journal.pone.0116381
Isolation and Functional Characterization of the Novel Clostridium botulinum Neurotoxin A8 Subtype
dc.contributor.authorKull, Skadi
dc.contributor.authorSchulz, Melanie
dc.contributor.authorStrotmeier, Jasmin Weisemann née
dc.contributor.authorKirchner, Sebastian
dc.contributor.authorSchreiber, Tanja
dc.contributor.authorBollenbach, Alexander
dc.contributor.authorDabrowski, Piotr Wojtek
dc.contributor.authorNitsche, Andreas
dc.contributor.authorKalb, Suzanne R.
dc.contributor.authorDorner, Martin
dc.contributor.authorBarr, John R.
dc.contributor.authorRummel, Andreas
dc.contributor.authorDorner, Brigitte
dc.date.accessioned2018-05-07T18:06:30Z
dc.date.available2018-05-07T18:06:30Z
dc.date.created2015-02-16
dc.date.issued2015-02-06none
dc.identifier.otherhttp://edoc.rki.de/oa/articles/re0ep9lc44LdU/PDF/21RMggibHbU.pdf
dc.identifier.urihttp://edoc.rki.de/176904/2018
dc.description.abstractBotulism is a severe neurological disease caused by the complex family of botulinum neurotoxins (BoNT). Based on the different serotypes known today, a classification of serotype variants termed subtypes has been proposed according to sequence diversity and immunological properties. However, the relevance of BoNT subtypes is currently not well understood. Here we describe the isolation of a novel Clostridium botulinum strain from a food-borne botulism outbreak near Chemnitz, Germany. Comparison of its botulinum neurotoxin gene sequence with published sequences identified it to be a novel subtype within the BoNT/A serotype designated BoNT/A8. The neurotoxin gene is located within an ha-orfX+ cluster and showed highest homology to BoNT/A1, A2, A5, and A6. Unexpectedly, we found an arginine insertion located in the HC domain of the heavy chain, which is unique compared to all other BoNT/A subtypes known so far. Functional characterization revealed that the binding characteristics to its main neuronal protein receptor SV2C seemed unaffected, whereas binding to membrane-incorporated gangliosides was reduced in comparison to BoNT/A1. Moreover, we found significantly lower enzymatic activity of the natural, full-length neurotoxin and the recombinant light chain of BoNT/A8 compared to BoNT/A1 in different endopeptidase assays. Both reduced ganglioside binding and enzymatic activity may contribute to the considerably lower biological activity of BoNT/A8 as measured in a mouse phrenic nerve hemidiaphragm assay. Despite its reduced activity the novel BoNT/A8 subtype caused severe botulism in a 63-year-old male. To our knowledge, this is the first description and a comprehensive characterization of a novel BoNT/A subtype which combines genetic information on the neurotoxin gene cluster with an in-depth functional analysis using different technical approaches. Our results show that subtyping of BoNT is highly relevant and that understanding of the detailed toxin function might pave the way for the development of novel therapeutics and tailor-made antitoxins.eng
dc.language.isoeng
dc.publisherRobert Koch-Institut, Biologische Sicherheit
dc.subjectHumanseng
dc.subjectMaleeng
dc.subjectAmino Acid Sequenceeng
dc.subjectMolecular Sequence Dataeng
dc.subjectGermany/epidemiologyeng
dc.subjectMiddle Agedeng
dc.subjectBotulism/microbiologyeng
dc.subjectBotulinum Toxins Type A/geneticseng
dc.subjectSequence Analysis DNAeng
dc.subjectBase Sequenceeng
dc.subjectDisease Outbreakseng
dc.subjectModels Moleculareng
dc.subjectProtein Bindingeng
dc.subjectBotulinum Toxins Type A/chemistryeng
dc.subjectBotulinum Toxins Type A/classificationeng
dc.subjectBotulinum Toxins Type A/metabolismeng
dc.subjectBotulism/epidemiologyeng
dc.subjectBotulism/pathologyeng
dc.subjectClostridium botulinum type A/geneticseng
dc.subjectFood Preserved/microbiologyeng
dc.subjectRNA Ribosomal 16S/geneticseng
dc.subjectSequence Homologyeng
dc.subject.ddc610 Medizin
dc.titleIsolation and Functional Characterization of the Novel Clostridium botulinum Neurotoxin A8 Subtype
dc.typeperiodicalPart
dc.identifier.urnurn:nbn:de:0257-10038782
dc.identifier.doi10.1371/journal.pone.0116381
dc.identifier.doihttp://dx.doi.org/10.25646/1943
local.edoc.container-titlePLoS ONE
local.edoc.container-textKull S, Schulz KM, Strotmeier JWn, Kirchner S, Schreiber T, et al. (2015) Isolation and Functional Characterization of the Novel Clostridium botulinum Neurotoxin A8 Subtype. PLoS ONE 10(2): e0116381.
local.edoc.fp-subtypeArtikel
local.edoc.type-nameZeitschriftenartikel
local.edoc.container-typeperiodical
local.edoc.container-type-nameZeitschrift
local.edoc.container-urlhttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0116381
local.edoc.container-publisher-namePublic Library of Science
local.edoc.container-volume10
local.edoc.container-issue2
local.edoc.container-year2015

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